JP2012056963A - Modulator of atp-binding cassette transporter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide modulators of ATP-binding cassette ('ABC') transporters or their fragments.SOLUTION: The modulators, which include cystic fibrosis transmembrane conductance regulator, of the ATP-binding cassette ('ABC') transporters or their fragments are provided. A composition for the modulators, and a method using the modulators are also provided. Methods of treating ABC transporter mediated diseases using the modulators are also provided.

Description

(Incorporation of related applications)
This application is filed on June 24, 2004, and is filed on November 22, 2004, US Provisional Patent Application No. 60 / 582,676, whose title is “MODULATORS OF ATP-BINDING CASSETT TRANSPORTERS”. In addition, US provisional patent application No. 60 / 630,127 whose title is “MODULATORS OF ATP-BINDING CASSETT TRANSPORTERS”; the title of the invention, filed on December 13, 2004, is “MODULATORS OF ATP-BINDING”. US Provisional Patent Application No. 60 / 635,674, “CASSETT TRANSPORTERS”; filed on March 3, 2005 with the title “MODULATORS OF ATP-BINDING CASSET” US Provisional Patent Application No. 60 / 658,219, “TRANSPORTERS”; and US Provisional Patent Application No. 60 /, filed March 11, 2005, with the title “MODULATORS OF ATP-BINDING CASSETT TRANSPORTERS”. 661,311; claim priority under 35 USC 119.

(Technical field of the invention)
The present invention relates to modulators of ATP binding cassette (“ABC”) transporters or fragments thereof, including cystic fibrosis membrane conductance regulators, compositions thereof, and methods of using the same. The invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

  ABC transporters are a family of membrane transporter proteins that regulate the transport of a wide variety of drugs, potentially toxic drugs, and xenobiotics, as well as anions. ABC transporters are homologous membrane proteins that bind to cellular adenosine triphosphate (ATP) and use cellular ATP for its specific activity. Some of these transporters have been discovered as multidrug resistance proteins (such as MDR1-P glycoprotein or multidrug resistance protein MRP1) and protect malignant cancer cells against chemotherapeutic agents. To date, 48 ABC transporters have been identified and classified into 7 families based on their sequence identity and function.

  ABC transporters regulate various important physiological roles in the body and provide protection against harmful environmental compounds. Because of this, they are useful for the treatment of diseases associated with deficiencies in the transporter, for the prevention of drug transport out of the target cell, and other cases where modulation of ABC transporter activity may be beneficial. Indicates an important potential drug target for intervention in disease.

One member of the ABC transporter family that is commonly associated with disease is CFTR, a cAMP / ATP-mediated anion channel. CFTR is expressed in a variety of cell types, including absorptive and secretory epithelial cells, in which CFTR regulates anion flux across the membrane and the activity of other ion channels and proteins. In epithelial cells, the normal function of CFTR is important for maintaining electrolyte transport throughout the body, including respiratory and digestive tissues. CFTR is composed of approximately 1480 amino acids that encode a protein composed of a tandem repeat of a transmembrane domain (each transmembrane domain contains 6 transmembrane helices) and a nucleotide binding domain. The two transmembrane domains are linked by a large polarity regulatory (R) domain that contains multiple phosphorylation sites, which regulate channel activity and cellular trafficking.

  The gene encoding CFTR has been identified and sequenced (see Non-Patent Document 1; Non-Patent Document 2; Non-Patent Document 3). A deficiency in this gene causes a CFTR mutation that results in cystic fibrosis (“CF”), which is the most common lethal genetic disease in humans. Cystic fibrosis affects approximately 1 in 2,500 infants in the United States. Of the total US population, up to 10 million people have one copy of a defective gene that apparently has no disease effects. In contrast, individuals with two copies of CF-related genes suffer from debilitating and lethal effects (including chronic lung disease) due to CF.

  In patients with cystic fibrosis, mutations in CFTR that are endogenously expressed in the respiratory epithelium result in decreased apical anion secretion, causing an imbalance in ionic and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lung and concomitant microbial infection, which ultimately causes death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency, which leads to death if left on taste treatment. Furthermore, the majority of men with cystic fibrosis are infertile. Fertility is reduced among women with cystic fibrosis. In contrast to the serious effects of two copies of CF-related genes, individuals with one copy of CF-related genes show increased resistance to cholera and increased resistance to dehydration resulting from diarrhea. This probably explains the relatively high frequency of CF genes in that population.

  Sequence analysis of the CFTR gene on the CF chromosome revealed mutations that cause various diseases (Non-patent document 3; Non-patent document 4; Non-patent document 5; Non-patent document 6). To date, mutations in the CF gene that cause more than 1000 diseases have been identified (http://www.genet.sickkids.on.cat/cftr/). The most common mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as ΔF508-CFTR. This mutation is present in about 70% of the causes of cystic fibrosis and is associated with severe disease.

  The deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly. This causes the mutant protein to leave the endoplasmic reticulum (ER) and not be transported to the plasma membrane. As a result, the number of channels present in the membrane is much less than that observed in cells expressing wild type CFTR. In addition to transport damage, this mutation results in defective channel gating. Together, the reduction in the number of channels in the membrane and defective gating results in a decrease in anion transport through the epithelium, leading to defective ion-fluid transport (8). However, studies have shown that a reduced number of ΔF508-CFTR in the membrane is functional despite being less than wild-type CFTR (Non-Patent Document 9; Denning et al. (Supra). ); Non-Patent Document 10). In addition to ΔF508-CFTR, other disease-causing mutations in CFTR that result in defective transport, defective synthesis, and / or defective channel gating alter anion secretion to increase disease progression and / or weight. Can be up-regulated or down-regulated to alter severity.

It is clear that CFTR transports various molecules in addition to anions, but this role (anion transport) represents an element in an important mechanism of transporting ions and water through the epithelium. Other iodine includes epithelial Na ⁺ channel, ENaC, Na ⁺ / 2Cl ⁻ / K ⁺ cotransporter, Na ⁺ −K ⁺ -ATPase pump, and basolateral membrane K ⁺ channel (which is chlorinated into cells Responsible for the uptake of product ions).

These elements work together to achieve directional transport through the epithelium through their selective expression and localization in the cell. Chloride ion absorption is performed by the cooperative activity of ENACl and CFTR present on the apical membrane and the Na ⁺ -K ⁺ -ATPase pump expressed on the basolateral surface of the cell. Secondary active transport of chloride ions from the luminal side results in the accumulation of intracellular chloride ions, which can then remain passively in the cells via Cl ^- channels, vectorial ) Generate transport. Na ⁺ / 2Cl
^The placement of the ⁻ / K ⁺ cotransporter, Na ⁺ −K ⁺ -ATPase pump, and K ⁺ channel on the basolateral membrane, and CFTR on the luminal side is responsible for the chloride ion via the CFTR on the luminal side. Regulate secretion. Since water is probably never actively transported by itself, the flow of water through the epithelium depends on a small transepithelial osmotic gradient generated by a large flow of sodium and chloride ions.

In addition to cystic fibrosis, modulation of CFTR activity is due to other diseases that are not directly caused by mutations in CFTR (eg, secretory diseases), and other protein folding diseases mediated by CFTR. Can be beneficial. These include, but are not limited to, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's syndrome. COPD is characterized by airflow limitation that is progressive and not fully reversible. Mutant or wild type CFTR activators provide a common treatment for mucus hypersecretion and impaired mucociliary clearance common in COPD. Specifically, increasing anion secretion through CFTR can facilitate fluid transport into the airway surface fluid, hydrate the mucus, and optimize periciliary fluid viscosity. This results in increased mucociliary clearance and reduced symptoms associated with COPD. Dry eye disease is characterized by decreased tear production and an abnormal fluid, protein, and mucus profile of the tear film. There are many causes of dry eye. Some of these include aging, Lasik (laser intracorneal cutting) ophthalmic surgery, arthritis, medications, chemical / thermal burns, allergies, and diseases (eg, cystic fibrosis and Sjogren's syndrome) Can be mentioned. Increased anion secretion via CFTR enhances fluid transport from corneal epithelial cells and from the secretory glands around the eye, increasing corneal hydration. This helps alleviate the symptoms associated with dry eye disease. Sjogren's syndrome is an autoimmune disease in which the immune system attacks the hydrogenic gland throughout the body, including the eyes, mouth, skin, respiratory tissue, liver, vagina, and stomach. Symptoms include dry eye, dry mouth, and vaginal dryness, and lung disease. The disease is also associated with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and polymyositis / dermatomyositis. Defective protein transport is thought to cause this disease and treatment options for this are limited. Modulators of CFTR activity can hydrate the various organs affected by the disease and help alleviate the associated symptoms.

  As noted above, deletion of residue 508 in ΔF508-CFTR can cause the nascent protein to fold correctly and cause the mutant protein to exit the endoplasmic reticulum (ER) and move to the plasma membrane. It is thought that we cannot do it. As a result, insufficient amounts of the mature protein are present in the plasma membrane, and chloride ion transport within epithelial tissue is significantly reduced. Indeed, this cellular phenomenon of ABC transporter defective endoplasmic reticulum (ER) processing by the endoplasmic reticulum (ER) mechanism is not only the basis of CF disease, but also the cause of a wide range of other isolated and inherited diseases. But it has been shown. Two ways in which the endoplasmic reticulum (ER) mechanism may be dysfunctional are the loss of coupling to export of those proteins from the endoplasmic reticulum (ER) or the endoplasmic reticulum of these defective / misfolded proteins (ER ) [Non-patent document 11; Non-patent document 12; Non-r patent document 13; Non-patent document 14; Non-patent document 15]. Diseases associated with the first type of endoplasmic reticulum (ER) dysfunction are cystic fibrosis (due to misfolded ΔF508-CFTR as described above), hereditary emphysema (α1-antitrypsin (non-Piz) Hereditary hemochromatosis, coagulation-fibrinolysis deficiency (eg protein C deficiency), type 1 hereditary angioedema, lipid processing deficiency (eg familial hypercholesterolemia, type 1 cairo Micronemia, abetalipoproteinemia, lysosomal storage diseases (eg, I-cell disease / pseudo-Hurler, mucopolysaccharidosis (due to lysosomal processing enzyme), Zanthof disease / Tay-Sachs disease (Due to β-hexosaminidase), type II Krigler-Najjar disease (in UDP-glucuronyl-sialyltransferase) ), Multiple endocrine disease / hyperinsulinemia, diabetes (caused by insulin receptor), laron dwarfism (caused by growth hormone receptor), myeloperoxidase deficiency, primary hypoparathyroidism ( Preproparathyroid hormone), melanoma (caused by tyrosinase), the latter type of disease associated with endoplasmic reticulum (ER) dysfunction is Glycanosis CDG type 1, hereditary emphysema (α1-anti Due to trypsin (PiZ variant), congenital hyperthyroidism, osteogenesis imperfecta (due to type I, type II, type IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen) ), ACT deficiency (due to α1-antichymotrypsin), diabetes insipidus (DI), neurophysinic (neur physal) DI (caused by vasopressin hormone / V2 receptor), neurological DI (caused by aquaporin II), Charcot-Marie-Tooth syndrome (caused by peripheral myelin protein 22), Merzbacher-Pelizeus disease, neurodegenerative disease ( For example, Alzheimer's disease (due to βAPP and presenilin), Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, some polyglutamine neuropathies (eg Huntington's disease), spinocerebellar Ataxia type I, spinal bulbar muscular atrophy, dentate nucleus red nucleus pallidal dystrophy and myotonic dystrophy), and spongiform encephalopathy (eg, hereditary Creutelfeldt-Jakob disease ( Prionta Is due to Scheinker syndrome (Prp processing defect)) - due to the Park protein processing defect), Fabry disease (due to lysosomal α- galactosidase A) and Sträussler.

  In addition to the up-regulation of CFTR activity, the decrease in anion secretion by CFTR modulators is associated with secretory diarrhea (epithelial water transport is dramatically increased as a result of chloride ion transport activated by secretagogues. ) May be beneficial for treatment. The mechanism involves an increase in cAMP and stimulation of CFTR.

  Although there are many causes of diarrhea, the major consequences of diarrheal disease resulting from excessive chloride ion transport are common to all, including dehydration, acidosis, impaired growth, and death.

  Acute and chronic diarrhea represents a major medical problem in many areas around the world. Diarrhea is an important cause of malnutrition and is a major cause in children younger than 5 years (5,000,000 deaths per year).

  Secretory diarrhea is also a dangerous condition in patients with acquired immune deficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD). Every year, 16 million travelers from developed countries to developing countries develop diarrhea. The severity and number of cases of diarrhea vary depending on the country and region where you travel.

  Diarrhea (also known as diarrhea or scours) in livestock and pets (eg, cows, pigs, and horses, sheep, goats, cats, and dogs) is a major cause of death in these animals. Diarrhea can arise from any major change (eg, weaning, or physical movement), as well as in response to various bacterial or viral infections, typically in the first few hours of an animal's life .

  The most common diarrhea causing bacterium is enterotoxic Escherichia coli (ETEC) with K99 pilus antigen. Common viral causes of diarrhea include rotavirus and coronavirus. Other infectious agents include Cryptosporidium, Rumble flagellate, and Salmonella, among others.

  Symptoms of rotavirus infection include watery stool, dehydration, and weakness. Coronavirus causes a relatively severe disease in newborn animals, which has a higher mortality rate than rotavirus infection. Often, however, young animals can be infected simultaneously with more than one virus, or can be simultaneously infected with a combination of viral and bacterial microorganisms. This dramatically increases the severity of diarrhea.

  Accordingly, there is a need for modulators of ABC transporter activity and compositions thereof that can be used to modulate ABC transporter activity in mammalian cell membranes.

  There is a need for methods for treating ABC transporter mediated diseases using such ABC transporter activity modulators.

  There is a need for methods for modulating ABC transporter activity in mammalian ex vivo cell membranes.

  There is a need for modulators of CFTR activity that can be used to modulate the activity of CFTR in mammalian cell membranes.

  There is a need for methods for treating CFTR-mediated diseases using such CFTR activity modulators.

  There is a need for methods for modulating CFTR activity in mammalian ex vivo cell membranes.

Gregory, R.A. J. et al. Nature (1990) 347: 382-386. Rich, D.C. P. Nature (1990) 347: 358-362. Riodan, J .; R. Science (1989) 245: 1066-1073. Cutting, G.M. R. Nature (1990) 346: 366-369. Dean, M.M. Cell (1990) 61: 863: 870. Kerem, BS. Science (1989) 245: 1073-1080. Kerem. B-S. Et al., Proc. Natl. Acad. Sci. USA (1990) 87: 8447-8451. Quinton, P.M. M.M. , FASEB J. et al. (1990) 4: 2709-2727 Dalemans et al., Nature London. (1991) 354: 526-528 Pasyk and Foskett, J. et al. Cell. Biochem. (1995) 270: 12347-50 Aridor M.M. Et al., Nature Med. (1999) 5'7), pp 745-751. Shasty, B.M. S. Et al., Neurochem. International (2003) 43, pp1-7 Rutishauser, J. et al. Swiss Med Wkly (2002) 132, pp 211-222. Morello, JP et al., TIPS (2000) 21, pp. 466-469 Bross. Et al., Human Mut. (1999) 14, pp. 186-198

(Summary of the Invention)
It has now been found that the compounds of the invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ABC transporter activity. These compounds have the general formula I:

Or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and Ar ¹ generally have the following classes and subclasses: In the description.

  These compounds and pharmaceutically acceptable compositions include cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, clot-fibrinolysis deficiency (eg, protein C deficiency), type I hereditary angioedema , Lipid processing deficiency (eg familial hypercholesterolemia, type I chyleemia, abetalipoproteinemia), lysosomal storage diseases (eg I-cell disease / pseudo-Harler syndrome, mucopolysaccharidosis, Sandhoff disease) / Tay-Sachs disease, type II Crigler-Najjar syndrome, multi-endocrine disorders / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypothyroidism, Melanoma, type I glycanosis CDG, hereditary emphysema, congenital thyroid machine Hypertension, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurophysical DI, neurogenic DI, Charcot-Marie-Tooth syndrome, Parizaeus Merzbacher (Perlizaeus-Merzbacher) disease), neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease), various polyglutamine neuropathies (eg Huntington's disease) , Type I spinocerebellar ataxia, spinal and medullary muscle atrophy, erythrocytic red nucleus pallidum and myotonic dystrophy), and spongiform encephalopathy (eg, hereditary Creutzfeldt-Jakob disease, Fabry disease) , Stausler Shaker (St treating or treating various diseases, disorders or conditions including, but not limited to, rassler-Scheinker disease, secretory diarrhea, polycystic kidney disease, COPD, dry eye syndrome or Sjogren's syndrome) Useful to reduce the degree.
For example, the present invention provides the following:
(Item 1)
Formula I

Or a pharmaceutically acceptable salt thereof, wherein:
Ar ¹ Is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally 5 Fused to a 12-membered monocyclic or bicyclic ring, aromatic ring, partially unsaturated ring, or saturated ring, wherein each ring is independently of nitrogen, oxygen, or sulfur Contains 0 to 4 selected heteroatoms, where Ar ¹ Are each -WR ^W Having m substituents independently selected from
W is a bond or optionally substituted C ₁ ~ C ₆ An alkylidene chain, wherein up to two methylene units of W are -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO ₂ -, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, -NR'SO ₂ Replaced by NR'- as needed and independently;
R ^W Are independently R ′, halo, NO ₂ , CN, CF ₃ Or OCF ₃ Is;
m is 0-5;
R ¹ , R ² , R ³ , R ⁴ And R ⁵ Each independently represents —X—R ^X Is;
X is a bond or optionally substituted C ₁ ~ C ₆ An alkylidene chain, wherein up to two methylene units of X are -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO ₂ -, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, -NR'SO ₂ Replaced by NR'- as needed and independently;
R ^X Are independently R ′, halo, NO ₂ , CN, CF ₃ Or OCF ₃ Is;
R ⁶ Is hydrogen, CF ₃ , -OR ', -SR', or an optionally substituted C1-8 aliphatic group;
R ⁷ Is hydrogen or -X-R ^X An optionally substituted C1-6 aliphatic group;
R ′ is hydrogen or a 3-8 membered saturated, partially unsaturated group having 0-3 heteroatoms independently selected from C1-C8 aliphatic groups, nitrogen, oxygen, or sulfur Or a fully unsaturated monocyclic ring, or an 8-12 membered saturated, partially unsaturated, having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur Or independently selected from optionally substituted groups selected from fully unsaturated bicyclic ring systems; or two occurrences of R ′ together with the atoms to which they are attached An optionally substituted 3-12 membered saturated, partially unsaturated or fully having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Forming an unsaturated monocyclic or bicyclic ring in
However:
i) R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Ar is hydrogen ¹ Is phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4 -Hydroxyphenyl, 2,4-dinitrophenyl, phenyl 3,5-dicarboxylate, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4- Methylphenyl, 3-carboxylate phenyl, 2-fluorophenyl, 3-fluorophenyl, 3-trifluoromethylphenyl, 3-ethoxyphenyl, 4-chlorophenyl, 3-methoxyphenyl, 4- Either dimethylaminophenyl or 3,4-dimethylphenyl In 2-ethylphenyl, neither 4-ethoxycarbonyl-phenyl;
ii) R ¹ , R ² , R ³ , R ⁵ , R ⁶ And R ⁷ Is hydrogen and R ⁴ Ar is methoxy ¹ Is not 2-fluorophenyl or 3-fluorophenyl;
iii) R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Is hydrogen and R ² Is 1,2,3,4-tetrahydroisoquinolin-1-yl-sulfonyl, Ar ¹ Is not 3-trifluoromethylphenyl;
iv) R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁷ Is hydrogen and R ⁶ Ar is methyl ¹ Is not phenyl;
v) R ¹ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Is hydrogen and R ² And R ³ Are methylenedioxy together, Ar ¹ Is 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl , Not 6-halo-benzothiazol-2-yl, 6-nitro-benzothiazol-2-yl, 6-thiocyano-benzothiazol-2-yl,
vi) R ¹ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Is hydrogen and R ² And R ³ Are methylenedioxy together, Ar ¹ Is substituted with -SO ₂ NHR ^XX R is not a 4-substituted phenyl which is R ^XX Is 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl;
vii) R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Ar is hydrogen ¹ Is not thiazol-2-yl, 1H-1,2,4-triazol-3-yl or 1H-1,3,4-triazol-2-yl;
viii) R ¹ , R ² , R ³ , R ⁵ , R ⁶ And R ⁷ Is hydrogen and R ⁴ Is CF ₃ , OMe, Chloro, SCF ₃ Or OCF ₃ If Ar ¹ Is 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl, 1-methyl-1,2- (1H) -pyrazole -5-yl, pyridin-2-yl, phenyl, N-methyl-imidazol-2-yl, imidazole 2-yl, 5-methyl-imidazol-2-yl, 1,3-oxazol- Neither 2-yl nor 1,3,5- (1H) -triazol-2-yl;
ix) R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Are each hydrogen, Ar ¹ May be pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl or 4-methoxy-6-methyl-1,3,5-triazin-2-yl; 5-bromo-pyridin-2 Not -yl, pyridin-2-yl or 3,5-dichloro-pyridin-2-yl;
x) R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁷ Are each hydrogen and R ⁶ Ar is hydroxy ¹ Is not 2,6-dichloro-4-aminosulfonyl-phenyl;
xi) R ² Or R ³ Ar is optionally substituted N-piperazyl, N-piperidyl, or N-morpholinyl, Ar ¹ Is not an optionally substituted ring selected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazol-2-yl, or indazolyl;
xii) R ² When is optionally substituted cyclohexylamino, Ar ¹ Is not optionally substituted phenyl, pyridyl or thiadiazolyl;
xiii) Ar ¹ Is not an optionally substituted tetrazolyl;
xiv) R ² , R ⁴ , R ⁵ , R ⁶ And R ⁷ Are each hydrogen and R ¹ And R ³ Both at the same time CF ₃ Ar, chloro, methyl, or methoxy ¹ Is not 4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl or [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] phenyl;
xv) R ¹ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Are each hydrogen and Ar ¹ R is thiazol-2-yl, R ² And R ³ All of these are isopropyl, chloro, CF ₃ Not;
xvi) Ar ¹ Is 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, phenyl, or 3-chlorophenyl,
a) R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ And R ⁷ When each is hydrogen ³ Is not methoxy; or
b) R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ When each is hydrogen ² Is not chloro; or
c) R ¹ , R ² , R ³ , R ⁵ , R ⁶ And R ⁷ When each is hydrogen ⁴ Is not methoxy; or
d) R ¹ , R ³ , R ⁴ , R ⁶ And R ⁷ Are each hydrogen and R ⁵ R is ethyl, R ² Is not chloro;
e) R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ And R ⁷ When each is hydrogen ³ Is not chloro;
xvi) R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ And R ⁷ Are each hydrogen and R ² Is CF ₃ Or OCF ₃ If Ar ¹ Is not [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] phenyl;
xvii) R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ And R ⁷ Are each hydrogen and R ³ Is hydrogen or CF ₃ If Ar ¹ Is -OCH ₂ CH ₂ Ph, -OCH ₂ CH ₂ (2-trifluoromethyl-phenyl), -OCH ₂ CH ₂ -Not (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) or substituted 1H-pyrazol-3-yl substituted phenyl; and
xviii) The following two compounds:

Or a pharmaceutically acceptable salt thereof.
(Item 2)
Ar ¹ Is the following:

Selected from;
Where ring A ₁ Is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or
A ₁ And A ₂ Together are 8- to 14-membered aromatic, bicyclic or tricyclic aryl rings, where each ring is independently selected from nitrogen, oxygen or sulfur. Containing heteroatoms,
Item 1. A compound according to item 1.
(Item 3)
A ₁ 3. A compound according to item 2, wherein N is an optionally substituted 6-membered aromatic ring having 0 to 4 heteroatoms, wherein the heteroatom is nitrogen.
(Item 4)
A ₁ The compound according to item 2, wherein is optionally substituted phenyl.
(Item 5)
A ₂ 3. The compound according to item 2, which is an optionally substituted 6-membered aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
(Item 6)
A ₂ The compound according to item 2, which is an optionally substituted 5-membered aromatic ring having 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
(Item 7)
A ₂ 3. The compound according to item 2, which is a 5-membered aromatic ring having 1 to 2 nitrogen atoms.
(Item 8)
A ₂ The following:


Selected from
Where ring A ₂ Is ring A through two adjacent ring atoms. ₁ The compound of item 2, which is condensed to
(Item 9)
R ⁵ And R ⁶ 2. The compound according to item 1, wherein is hydrogen.
(Item 10)
R ³ And R ⁴ Are simultaneously hydrogen; R ¹ Is hydrogen or —OH; and R ² 10. The compound according to item 9, wherein is hydrogen or fluoro.
(Item 11)
R ⁷ Item 11. The compound according to Item 10, wherein is hydrogen.
(Item 12)
WR ^W Each occurrence of is independently -C1-C3 alkyl, C1-C3 perhaloalkyl, -O (C1-C3 alkyl), -CF ₃ , -OCF ₃ , -SCF ₃ , -F, -Cl, -Br, or -COOR ', -COR', -O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′) (R ′), — (CH ₂ ) ₂ OR ',-(CH ₂ ) OR ′, optionally substituted monocyclic or bicyclic aromatic ring, optionally substituted aryl sulfone, optionally substituted 5-membered heteroaryl ring, —N ( R ′) (R ′), — (CH ₂ ) ₂ N (R ′) (R ′) or — (CH ₂ 2. The compound according to item 1, which is N (R ′) (R ′).
(Item 13)
WR ^W Each occurrence of halo, cyano, CF ₃ , CHF ₂ , OCHF ₂ , Me, Et, CH (Me) ₂ CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl, SMe, SCF ₃ , SCHF ₂ , SEt, CH ₂ CN, NH ₂ , NHMe, N (Me) ₂ , NHEt, N (Et) ₂ , C (O) CH ₃ , C (O) Ph, C (O) NH ₂ , SPh, SO ₂ -(Amino-pyridyl), SO ₂ NH ₂ , SO ₂ Ph, SO ₂ NHPh, SO ₂ -N-morpholino, SO ₂ -N-pyrrolidyl, N-pyrrolyl, N-morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino) methyl, 4-methyl-2,4-dihydro-pyrazol-3-on-2-yl, benzo Imidazol-2-yl, furan-2-yl, 4-methyl-4H- [1,2,4] triazol-3-yl, 3- (4′-chlorophenyl)-[1,2,4] oxadiazole- 5-yl, NHC (O) Me, NHC (O) Et, NHC (O) Ph, NHSO ₂ Me, 2-indolyl, 5-indolyl, -CH ₂ CH ₂ OH, -OCF ₃ , O- (2,3-dimethylphenyl), 5-methylfuryl, -SO ₂ -N-piperidyl, 2-tolyl, 3-tolyl, 4-tolyl, O-butyl, NHCO ₂ C (Me) ₃ , CO ₂ C (Me) ₃ , Isopropenyl, n-butyl, O- (2,4-dichlorophenyl), NHSO ₂ PhMe, O- (3-chloro-5-trifluoromethyl-2-pyridyl), phenylhydroxymethyl, 2,5-dimethylpyrrolyl, NHCOCH ₂ C (Me) ₃ O- (2-tert-butyl) phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 4-hydroxymethylphenyl, 4-dimethylaminophenyl, 2-trifluoromethylphenyl, 3-trifluoromethyl Phenyl, 4-trifluoromethylphenyl, 4-cyanomethylphenyl, 4-isobutylphenyl, 3-pyridyl, 4-pyridyl, 4-isopropylphenyl, 3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- Methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-methylthiophenyl, 4-methylthiophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl , 2,6-Dimethoxyv Alkenyl, 3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF ₃ -Phenyl, 3-trifluoromethoxy-phenyl, 4-trifluoromethoxyphenyl, 2-phenoxyphenyl, 4-phenoxyphenyl, 2-fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl, 5- Isopropyl-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2 , 5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluoro-phenyl, 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3, 4-dichlorophenyl, 2,4-dichloro Enyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-isopropyloxycarbonylphenyl, 3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfinyl-phenyl, 4-methanesulfonyl-phenyl, 4 -N- (2-N, N-dimethylaminoethyl) carbamoylphenyl, 5-acetyl-2-thienyl, 2-benzothienyl, 3-benzothienyl, furan-3-yl, 4-methyl-2-thienyl, 5 -Cyano-2-thienyl, N'-phenylcarbonyl-N-piperazinyl, -NHCO ₂ Et, -NHCO ₂ Me, N-pyrrolidinyl, -NHSO ₂ (CH ₂ ) ₂ N-piperidine, -NHSO ₂ (CH ₂ ) ₂ N-morpholine, -NHSO ₂ (CH ₂ ) ₂ N (Me) ₂ , COCH ₂ N (Me) COCH ₂ NHMe, -CO ₂ Et, O-propyl, -CH ₂ CH ₂ NHCO ₂ C (Me) ₃ , Hydroxy, aminomethyl, pentyl, adamantyl, cyclopentyl, ethoxyethyl, C (Me) ₂ CH ₂ OH, C (Me) ₂ CO ₂ Et, -CHOHMe, CH ₂ CO ₂ Et, -C (Me) ₂ CH ₂ NHCO ₂ C (Me) ₃ , O (CH ₂ ) ₂ OEt, O (CH ₂ ) ₂ OH, CO ₂ Me, hydroxymethyl, 1-methyl-1-cyclohexyl, 1-methyl-1-cyclooctyl, 1-methyl-1-cycloheptyl, C (Et) ₂ C (Me) ₃ , C (Et) ₃ , CONHCH ₂ CH (Me) ₂ , 2-aminomethyl-phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyl, cyclohexyl, 4-methylpiperidinyl, -OCO ₂ Me, -C (Me) ₂ CH ₂ NHCO ₂ CH ₂ CH (Me) ₂ , -C (Me) ₂ CH ₂ NHCO ₂ CH ₂ CH ₂ CH ₃ , -C (Me) ₂ CH ₂ NHCO ₂ Et, -C (Me) ₂ CH ₂ NHCO ₂ Me, -C (Me) ₂ CH ₂ NHCO ₂ CH ₂ C (Me) ₃ , -CH ₂ NHCOCF ₃ , -CH ₂ NHCO ₂ C (Me) ₃ , -C (Me) ₂ CH ₂ NHCO ₂ (CH ₂ ) ₃ CH ₃ , C (Me) ₂ CH ₂ NHCO ₂ (CH ₂ ) ₂ OMe, C (OH) (CF ₃ ) ₂ , -C (Me) ₂ CH ₂ NHCO ₂ CH ₂ -Tetrahydrofuran-3-yl, C (Me) ₂ CH ₂ O (CH ₂ ) ₂ 13. A compound according to item 12, selected from OMe or 3-ethyl-2,6-dioxopiperidin-3-yl.
(Item 14)
The compound is of formula HA or formula HB:

The compound of item 2 which has these.
(Item 15)
The compound is of formula IIIA, formula IIIB, formula IIIC, formula IIID, or formula IIIE:

Where:
X ₁ , X ₂ , X ₃ , X ₄ And X ₅ Each is independently selected from CH or N; and
X ₆ Is O, S, or NR ′,
Item 3. A compound according to item 2.
(Item 16)
X ₁ , X ₂ , X ₃ , X ₄ And X ₅ WR ^W 16. A compound according to item 15, which is optionally substituted phenyl together with and m.
(Item 17)
X ₁ , X ₂ , X ₃ , X ₄ And X ₅ Together in a compound of formula IIIA:


16. A compound according to item 15, which is an optionally substituted ring selected from.
(Item 18)
X ₁ , X ₂ , X ₃ , X ₄ , X ₅ Or X ₆ Is ring A in the compound of formula IIIB, formula IIIC, formula IIID, or formula IIIE ₂ With:





16. A compound according to item 15, which is an optionally substituted ring selected from.
(Item 19)
The compound is of formula IVA, formula IVB, or formula IVC:

16. The compound according to item 15, wherein
(Item 20)
Ring A ₂ Is optionally substituted, saturated, unsaturated, or aromatic, 5-7 membered ring, 0-3 heteroatoms selected from O, S, or N Item 20. The compound according to Item 19, having an atom.
(Item 21)
The compound is of the formula VA-I:

Where WR ^W2 And WR ^W4 Each of which is hydrogen, CN, CF ₃ , Halo, C1-C6 linear or branched alkyl, 3-12 membered cycloaliphatic, phenyl, C5-C10 heteroaryl or C3-C7 heterocyclic, The ring has up to 3 heteroatoms selected from O, S, or N, and the WR ^W2 And WR ^W4 Each independently is optionally substituted with up to three substituents, the substituents being —OR ′, —CF ₃ , -OCF ₃ , SR ′, S (O) R ′, SO ₂ R ', -SCF ₃ , Halo, CN, -COOR ', -COR', -O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′) (R ′), — (CH ₂ ) ₂ OR ',-(CH ₂ ) OR ', CH ₂ CN, optionally substituted phenyl or phenoxy, -N (R ') (R'), -NR'C (O) OR ', -NR'C (O) R',-(CH ₂ ) ₂ N (R ′) (R ′) or — (CH ₂ ) N (R ′) (R ′);
WR ^W5 Is hydrogen, -OH, NH ₂ , CN, CHF ₂ , NHR ′, N (R ′) ₂ , -NHC (O) R ', -NHC (O) OR', NHSO ₂ R ', -OR', CH ₂ OH, CH ₂ N (R ') ₂ , C (O) OR ', SO ₂ NHR ', SO ₂ N (R ') ₂ Or CH ₂ Selected from NHC (O) OR 'or WR ^W4 And WR ^W5 Together form a 5-7 membered ring containing 1-3 heteroatoms selected from N, O, or S, wherein the ring contains up to 3 WR ^W Optionally substituted with a substituent,
20. The compound according to item 19.
(Item 22)
WR ^W2 And WR ^W4 Each of which is hydrogen, CN, CF ₃ WR, independently selected from halo, C1-C6 linear or branched alkyl, 3-12 membered cycloaliphatic, or phenyl, ^W2 And WR ^W4 Each independently is optionally substituted with up to three substituents, the substituents being —OR ′, —CF ₃ , -OCF ₃ , -SCF ₃ , Halo, -COOR ', -COR', -O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′) (R ′), — (CH ₂ ) ₂ OR ',-(CH ₂ ) OR ′, optionally substituted phenyl, —N (R ′) (R ′), —NC (O) OR ′, —NC (O) R ′, — (CH ₂ ) ₂ N (R ′) (R ′) or — (CH ₂ ) N (R ′) (R ′);
WR ^W5 Is hydrogen, -OH, NH ₂ , CN, NHR ′, N (R ′) ₂ , -NHC (O) R ', -NHC (O) OR', NHSO ₂ R ', -OR', CH ₂ OH, C (O) OR ', SO ₂ NHR 'or CH ₂ Selected from NHC (O) O— (R ′),
Item 22. The compound according to Item 21.
(Item 23)
WR ^W2 Is a phenyl ring optionally substituted with up to 3 substituents, the substituents being —OR ′, —CF ₃ , -OCF ₃ , SR ′, S (O) R ′, SO ₂ R ', -SCF ₃ , Halo, CN, -COOR ', -COR', -O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′) (R ′), — (CH ₂ ) ₂ OR ',-(CH ₂ ) OR ', CH ₂ CN, optionally substituted phenyl or phenoxy, -N (R ') (R'), -NR'C (O) OR ', -NR'C (O) R',-(CH ₂ ) ₂ N (R ′) (R ′) or — (CH ₂ ) Selected from N (R ′) (R ′);
WR ^W4 Is C1-C6 straight or branched alkyl; and
WR ^W5 Is OH,
Item 23. The compound according to Item 22.
(Item 24)
WR ^W2 And WR ^W4 Each of which is CF ₃ 24. A compound according to item 22, independently selected from: halo, CN, or C1-C6 linear or branched alkyl.
(Item 25)
WR ^W2 And WR ^W4 Are optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethyl-2-hydroxyethyl, 1,1-dimethyl-2- (ethoxy 25. A compound according to item 24, independently selected from carbonyl) -ethyl, 1,1-dimethyl-3- (t-butoxycarbonyl-amino) propyl, or n-pentyl.
(Item 26)
WR ^W2 And WR ^W4 26. A compound according to item 25, wherein each of is a C1-C6 linear or branched alkyl.
(Item 27)
WR ^W5 But hydrogen, CHF ₂ , NH ₂ , CN, NHR ′, N (R ′) ₂ , CH ₂ N (R ') ₂ , -NHC (O) R ', -NHC (O) OR', -OR ', C (O) OR', or SO ₂ Item 22. The compound according to Item 21, selected from NHR '.
(Item 28)
WR ^W5 But hydrogen, NH ₂ , CN, CHF ₂ , NH (C1-C6 alkyl), N (C1-C6 alkyl) ₂ , -NHC (O) (C1-C6 alkyl), -CH ₂ NHC (O) O (C1-C6 alkyl), -NHC (O) O (C1-C6 alkyl), -OH, -O (C1-C6 alkyl), C (O) O (C1-C6 alkyl), CH ₂ O (C1-C6 alkyl) or SO ₂ NH ₂ The compound according to item 21, selected from:
(Item 29)
WR ^W5 -OH, OMe, NH ₂ , -NHMe, -N (Me) ₂ , -CH ₂ NH ₂ , CH ₂ OH, NHC (O) OMe, NHC (O) OEt, CN, CHF ₂ , -CH ₂ NHC (O) O (t-butyl), -O- (ethoxyethyl), -O- (hydroxyethyl), -C (O) OMe, or -SO ₂ NH ₂ 29. The compound according to item 28, selected from
(Item 30)
The compound has the following characteristics:
a. WR ^W2 Is hydrogen;
b. WR ^W4 Is a C1-C6 linear or branched, alkyl or monocyclic aliphatic or bicyclic aliphatic; and
c. WR ^W5 Is hydrogen, CN, CHF ₂ , NH ₂ , NH (C1-C6 alkyl), N (C1-C6 alkyl) ₂ , -NHC (O) (C1-C6 alkyl), -NHC (O) O (C1-C6 alkyl), -CH ₂ C (O) O (C1-C6 alkyl), -OH, -O (C1-C6 alkyl), C (O) O (C1-C6 alkyl), or SO ₂ NH ₂ Being selected from,
28. The compound of item 21, having one, preferably more, or more preferably all.
(Item 31)
The compound has the following characteristics:
a. WR ^W2 Is halo, C1-C6 alkyl, CF ₃ , CN, or phenyl optionally substituted with up to 3 substituents, wherein the substituents are selected from C1-C4 alkyl, —O (C1-C4 alkyl), or halo;
b. WR ^W4 But CF ₃ Halo, C1-C6 alkyl or C6-C10 cycloaliphatic; and
c. WR ^W5 OH, NH ₂ , NH (C1-C6 alkyl), or N (C1-C6 alkyl),
28. The compound of item 21, having one, preferably more, or more preferably all.
(Item 32)
The compound is of the formula VA-2:

Where Y is CH ₂ , C (O) O, C (O), or S (O) ₂ And the compound of item 19, wherein m is 0-4.
(Item 33)
The compound is of the formula VA-3:

Where: Q is W; R ^Q But R ^W 20. The compound according to item 19, wherein m is 0-4; and n is 0-4.
(Item 34)
The compound is of the formula VA-4:

20. The compound according to item 19, which has
(Item 35)
The compound is of the formula VA-5:

The compound according to item 19, wherein: m is 0-4.
(Item 36)
The compound is of formula VA-6:

Where:
Ring B has up to n -QR ^Q A 5-7 membered, monocyclic or bicyclic, heterocyclic or heteroaryl ring, optionally substituted with
Q is W;
R ^Q But R ^W Is;
m is 0-4; and
n is 0-4.
20. The compound according to item 19.
(Item 37)
Ring B is a 5-7 membered monocyclic heterocyclic ring having up to 2 heteroatoms selected from O, S, or N, wherein the ring is up to n -Q- R ^Q 40. The compound of item 36, wherein the compound is optionally substituted.
(Item 38)
Ring B is a 5-6 membered monocyclic heteroaryl ring having up to 2 heteroatoms selected from O, S, or N, the ring comprising up to n —Q—R ^Q 40. The compound of item 36, wherein the compound is optionally substituted.
(Item 39)
Ring B is N-morpholinyl, N-piperidinyl, 4-benzoyl-piperazin-1-yl, pyrrolidin-1-yl, or 4-methyl-piperidin-1-yl, benzimidazol-2-yl, 5-methyl- Furan-2-yl, 2,5-dimethyl-pyrrol-1-yl, pyridin-4-yl, indol-5-yl, indol-2-yl, 2,4-dimethoxy-pyrimidin-5-yl, furan- 2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl-thien-2-yl, 5-cyano-thien-2-yl, 3-chloro 40. The compound of item 36, selected from -5-trifluoromethyl-pyridin-2-yl.
(Item 40)
The compound is of formula V-B-1:

Where:
Q ₁ And Q ₃ One of these is N (WR ^W ) And Q ₁ And Q ₃ Of the other is O, S, or N (WR ^W ) Selected from;
Q ₂ Is C (O), CH ₂ -C (O), C (O) -CH ₂ , CH ₂ , CH ₂ -CH ₂ , CF ₂ Or CF ₂ -CF ₂ And; and
m is 0-3,
20. The compound according to item 19.
(Item 41)
Q ₃ But N (WR ^W ) Where WR ^W 41. A compound according to item 40, which is hydrogen, C1-C6 aliphatic, C (O) C1-C6 aliphatic, or C (O) OC1-C6 aliphatic.
(Item 42)
Q ₂ Is C (O), CH ₂ , CH ₂ -CH ₂ And Q ₁ 42. The compound according to item 41, wherein is O.
(Item 43)
The compound is of the formula VB-2:

Where:
R ^W1 Is hydrogen or C1-C6 aliphatic;
R ^W3 Each is hydrogen or C1-C6 aliphatic;
Or both R ^W3 Together form a heterocyclic ring having up to 2 heteroatoms selected from C3-C6 cycloalkyl, or O, S or NR ', which ring is up to 2 WR ^W Optionally substituted with a substituent; and
m is 0-4.
20. The compound according to item 19.
(Item 44)
WR ^W1 44. The compound of item 43, wherein is hydrogen, C1-C6 aliphatic, C (O) C1-C6 aliphatic, or C (O) OC1-C6 aliphatic.
(Item 45)
Each R ^W3 Is hydrogen, C1-C4 alkyl; or both R ^W3 Together form a C3-C6 cycloaliphatic ring, or a 5-7 membered heterocyclic ring having up to 2 heteroatoms selected from O, S, or N, wherein Cycloaliphatic or heterocyclic rings are WR ^W1 44. A compound according to item 43, optionally substituted with up to 3 substituents selected from
(Item 46)
The compound is of the formula VB-3:

Where:
Q ₄ Is a bond, C (O), C (O) O, or S (O) ₂ Is;
R ^W1 Is hydrogen or C1-C6 aliphatic; and
m is 0-4.
20. The compound according to item 19.
(Item 47)
The compound is of the formula VB-4:

Where:
20. The compound according to item 19, wherein m is 0-4.
(Item 48)
The compound is of the formula VB-5:

Where:
Ring A ₂ Is a phenyl or 5-6 membered heteroaryl ring, ring A ₂ And ring A ₂ The phenyl rings fused to ^W Having up to 4 substituents independently selected from; and
m is 0-4.
20. The compound according to item 19.
(Item 49)
Ring A ₂ But:

49. The compound according to item 48, wherein the ring is optionally substituted.
(Item 50)
The compound is of the formula VB-5-a:

Where:
G ₄ Is hydrogen, halo, CN, CF ₃ , CHF ₂ , CH ₂ F, optionally substituted C1-C6 aliphatic, aryl-C1-C6 alkyl, or phenyl, where G ₄ Up to 4 WR ^W Optionally substituted with a substituent; up to two methylene units of the C1-C6 aliphatic or C1-C6 alkyl are -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, Or -NR'SO ₂ Replaced by NR'- as necessary;
G ₅ Is hydrogen or optionally substituted C1-C6 aliphatic;
The indole ring system is WR ^W Further optionally substituted with up to three substituents independently selected from:
20. The compound according to item 19.
(Item 51)
G ₄ Is hydrogen and G ₅ Is a C1-C6 aliphatic, which is C1-C6 alkyl, halo, cyano, or CF ₃ And up to two methylene units of C1-C6 aliphatic or C1-C6 alkyl are optionally substituted with -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, Or -NR'SO ₂ 51. A compound according to item 50, optionally substituted with NR'-.
(Item 52)
G ₄ Is hydrogen and G ₅ Is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH ₂ C (O) OMe, (CH ₂ ) ₂ 51. The compound according to item 50, which is NHC (O) O-tert-But or cyclopentyl.
(Item 53)
G ₅ Is hydrogen and G ₄ Is halo, C1-C6 aliphatic or phenyl, which is C1-C6 alkyl, halo, cyano, or CF ₃ Up to two methylene units of the C1-C6 aliphatic or C1-C6 alkyl optionally substituted with -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, Or -NR'SO ₂ 51. A compound according to item 50, optionally substituted with NR'-.
(Item 54)
G ₅ Is hydrogen and G ₄ Are halo, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C (O) NH (CH ₂ ) ₂ -NMe ₂ ) -Phenyl, 2-methoxy-4-chloro-phenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, or piperidin-1-yl 51. A compound according to item 50, which is carbonyl.
(Item 55)
2. The compound according to item 1, wherein the compound is selected from Table 1.
(Item 56)
Formula AI:

Or a salt thereof;
here:
G ₁ Is hydrogen, R ′, C (O) R ′, C (S) R ′, S (O) R ′, S (O) ₂ R ′, Si (CH ₃ ) ₂ R ′, P (O) (OR ′) ₃ , P (S) (OR ') ₃ Or B (OR ') ₂ Is;
G ₂ Are halo, CN, CF ₃ , Isopropyl, or phenyl, which is WR ^W Optionally substituted with up to 3 substituents independently selected from: wherein W and R ^W Is as defined above with respect to Formula I and embodiments thereof;
G ₃ Is isopropyl or C ₃ ~ C ₁₀ A cycloaliphatic ring, the G ₃ WR ^W Optionally substituted with up to 3 substituents independently selected from: wherein W and R ^W Is as defined above with respect to Formula I and embodiments thereof;
However, G ₁ Is methoxy and G ₃ Is tert-butyl, G ₂ Is not 2-amino-4-methoxy-5-tert-butyl-phenyl.
(Item 57)
G ₁ Is hydrogen;
G ₂ Is halo or isopropyl, which isopropyl is optionally substituted with up to 3 substituents independently selected from R ′; and
G ₃ Is isopropyl or a C3-C10 cycloaliphatic ring, the G ₃ Is optionally substituted with up to 3 substituents independently selected from R ′,
57. The compound according to item 56.
(Item 58)
G ₁ Is hydrogen;
G ₂ Is halo, preferably fluoro; and
G ₃ Is a C3-C10 cycloaliphatic ring, and the G ₃ Is optionally substituted with up to three substituents independently selected from methyl, ethyl, propyl, or butyl,
58. The compound according to item 57.
(Item 59)
G ₁ Is hydrogen;
G ₂ Is CN, halo, or CF ₃ And; and
G ₃ Is isopropyl or a C3-C10 cycloaliphatic ring, the G ₃ Is optionally substituted with up to 3 substituents independently selected from R ′,
57. The compound according to item 56.
(Item 60)
G ₁ Is hydrogen;
G ₂ Are —OC1-C4 alkyl, CF ₃ Phenyl optionally substituted with up to 3 substituents independently selected from, halo, or CN; and
G ₃ Is isopropyl or a C3-C10 cycloaliphatic ring, the G ₃ Is optionally substituted with up to 3 substituents independently selected from R ′,
57. The compound according to item 56.
(Item 61)
G ₃ 59. The compound according to item 56, wherein is selected from optionally substituted cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.
(Item 62)
G ₃ 59. The compound of item 56, wherein is a C3-C8 branched aliphatic chain.
(Item 63)
Formula A-II:

Or a salt thereof, wherein:
G ₄ Is hydrogen, halo, CN, CF ₃ , CHF ₂ , CH ₂ F, optionally substituted C1-C6 aliphatic, aralkyl, or up to 4 WR ^W A phenyl ring optionally substituted with a substituent;
G ₅ Is hydrogen or optionally substituted C1-C6 aliphatic;
However, G ₄ And G ₅ And both are not hydrogen at the same time;
The indole ring system is WR ^W Further optionally substituted with up to three substituents selected from
Compound.
(Item 64)
G ₄ Is hydrogen and G ₅ Is a C1-C6 aliphatic, which is C1-C6 alkyl, halo, cyano, or CF ₃ And up to two methylene units of the C1-C6 aliphatic or C1-C6 alkyl are optionally substituted with -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, Or -NR'SO ₂ 64. Compound according to item 63, optionally substituted with NR′-.
(Item 65)
G ₄ Is hydrogen and G ₅ Is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH ₂ C (O) OMe, (CH ₂ ) ₂ 64. A compound according to item 63, which is NHC (O) O-tert-But or cyclopentyl.
(Item 66)
G ₅ Is hydrogen and G ₄ Is halo, C1-C6 aliphatic or phenyl, which is C1-C6 alkyl, halo, cyano, or CF ₃ And optionally up to two methylene units of the C1-C6 aliphatic or C1-C6 alkyl are -CO-, -CONR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'CO-, -S-, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, Or -NR'SO ₂ 64. Compound according to item 63, optionally substituted with NR′-.
(Item 67)
G ₅ Is hydrogen and G ₄ Halo, CF ₃ , Ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C (O) NH (CH ₂ ) ₂ -NMe ₂ 2-methoxy-4-chloro-phenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, or piperidin-1-ylcarbonyl. 64. The compound according to item 63.
(Item 68)
A pharmaceutical composition comprising a compound of formula I according to item 1 and a pharmaceutically acceptable carrier or adjuvant.
(Item 69)
70. The composition of item 68, wherein the composition comprises a further agent selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, CFTR modulators, or nutrients.
(Item 70)
A method of modulating ABC transporter activity, wherein the method comprises converting the ABC transporter to formula (I):

Contacting with a compound of or a pharmaceutically acceptable salt thereof, wherein:
Ar ¹ Is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which ring is a 5-12 membered monocyclic ring Optionally fused to an aromatic, partially unsaturated, or saturated ring of the formula or bicyclic ring, each ring independently selected from nitrogen, oxygen, or sulfur Containing 0 to 4 heteroatoms ¹ Has m substituents, each substituent being -WR ^W Selected independently from;
W is a bond or optionally substituted C ₁ ~ C ₆ An alkylidene chain, and up to two methylene units of W are -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO ₂ -, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, -NR'SO ₂ Replaced by NR'- as needed and independently;
R ^W Are independently R ′, halo, NO ₂ , CN, CF ₃ Or OCF ₃ Is;
m is 0-5;
R ¹ , R ² , R ³ , R ⁴ And R ⁵ Each independently represents —X—R ^X Is;
X is a bond or optionally substituted C ₁ ~ C ₆ An alkylidene chain, and up to two methylene units of X are -CO-, -CS-, -COCO-, -CONR'-, -CONR'NR'-, -CO ₂ -, -OCO-, -NR'CO ₂ -, -O-, -NR'CONR'-, -OCONR'-, -NR'NR ', -NR'NR'CO-, -NR'CO-, -S-, -SO, -SO ₂ -, -NR'-, -SO ₂ NR'-, NR'SO ₂ -, Or -NR'SO ₂ Replaced by NR'- as needed and independently;
R ^X Are independently R ′, halo, NO ₂ , CN, CF ₃ Or OCF ₃ Is;
R ⁶ Is hydrogen, CF ₃ , -OR ', -SR', or optionally substituted C _1-8 An aliphatic group;
R ⁷ Is hydrogen or -XR ^X C optionally substituted with _1-6 An aliphatic group;
R ′ is independently selected from hydrogen or an optionally substituted group, which group is C ₁ ~ C ₈ 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from aliphatic groups, nitrogen, oxygen, or sulfur An 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur Or two occurrences of R ′ are independently selected from nitrogen, oxygen, or sulfur, together with the atom to which R ′ is attached. Forming optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic rings having 1 heteroatom,
Method.
(Item 71)
71. A method according to item 70, wherein the ABC transporter is CFTR.
(Item 72)
A method of treating or reducing the severity of a disease in a patient, said disease comprising cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, clot-fibrinolysis deficiency (e.g. , Protein C deficiency), type I hereditary angioedema, lipid processing deficiency (eg familial hypercholesterolemia, type I cholestasis, abetalipoproteinemia), lysosomal storage diseases (eg I-cells) Disease / Pseudo-Harler Syndrome, Mucopolysaccharidosis, Sandhoff's Disease / Tay-Sachs Disease, Type II Krigler-Najjar Disease, Polygonal Endocrine Disorder / Hyperinsulinemia, Diabetes Mellitus, Laron Dwarfism, Myeloperoxidase Deficiency, Primary hypoparathyroidism, melanoma, type I glycanosis CDG, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurofiscal DI, neurogenic DI, Charcot-Marie-Tooth syndrome, Parizaeus-Merzbacher's disease), neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive nuclear on Paralysis, Pick's disease), various polyglutamine neuropathies (eg Huntington's disease, type I spinocerebellar ataxia, spinal and medullary muscle atrophy, dentate nucleus red nucleus pallidum and myotonic dystrophy) And a method of spongiform encephalopathy (eg, hereditary Creutzfeldt-Jakob disease (due to deficiency in prion protein processing), Fabry disease, Stausler-Schönker syndrome, COPD, dry eye syndrome or Sjogren's syndrome) Provides the patient with an effective amount of a compound of formula I according to item 70 Administering a step of administering.
(Item 73)
A kit for use in measuring the activity of an ABC transporter or fragment thereof in a biological sample in vitro or in vivo, the kit comprising:
(I) a composition comprising a compound of formula (I) according to item 70;
(Ii)
a) contacting the composition with the biological sample;
b) measuring the activity of the ABC transporter or fragment thereof;
Instructions about the
A kit comprising:
(Item 74)
a) contacting an additional composition with the biological sample;
b) measuring the activity of said ABC transporter or fragment thereof in the presence of said further compound; and
c) comparing the activity of the ABC transporter or fragment thereof in the presence of the further compound to the density of the ABC transporter in the presence of the compound of formula (I);
74. A kit according to item 73, further comprising instructions for.
(Item 75)
75. A kit according to item 74, wherein the kit is used for measuring the density of CFTR.

(Detailed description of the invention)
I. General Description of Compounds of the Invention
The present invention relates to compounds of formula I useful as modulators of ABC transporter activity:

Or for pharmaceutically acceptable salts thereof, where:
Ar ¹ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is a 5-12 membered ring. Are optionally fused to mono- or bicyclic rings, aromatic rings, partially unsaturated rings, or saturated rings, each ring independently of nitrogen, oxygen, or sulfur Containing 0 to 4 selected heteroatoms, Ar ¹ has m substituents, each substituent being independently selected from —WR ^W ;
W is a C ₁ -C ₆ alkylidene chain that is bonded or optionally substituted, and up to two methylene units can be —CO—, —CS—, —COCO—, —CONR′—, — _{CONR'NR '-, - CO 2 -} , - OCO -, - NR'CO 2 -, - O -, - NR'CONR' -, - OCONR '-, - NR'NR', - NR'NR'CO -, - NR'CO -, - S -, - sO, -SO 2 -, - NR '-, - sO 2 NR' -, NR'SO 2 -, or -NR'SO ₂ NR'- needs by Replaced accordingly and independently;
R ^W is independently R ′, halo, NO ₂ , CN, CF ₃ , or OCF ₃ ;
m is 0-5;
Each of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is independently -X-R ^X ;
X is a bond or optionally substituted C ₁ -C ₆ alkylidene chain, and up to two methylene units of —CO—, —CS—, —COCO—, —CONR′—, — _{CONR'NR '-, - CO 2 -} , - OCO -, - NR'CO 2 -, - O -, - NR'CONR' -, - OCONR '-, - NR'NR', - NR'NR'CO -, - NR'CO -, - S -, - sO, -SO 2 -, - NR '-, - sO 2 NR' -, NR'SO 2 -, or -NR'SO ₂ NR'- needs by Replaced accordingly and independently;
R ^X is independently R ′, halo, NO ₂ , CN, CF ₃ , or OCF ₃ ;
R ⁶ is hydrogen, CF ₃ , —OR ′, —SR ′, or an optionally substituted C _1-6 aliphatic group;
R ⁷ is hydrogen or a C _1-6 aliphatic group optionally substituted with —X—R ^X ;
R ′ is independently selected from hydrogen or optionally substituted groups, the groups being 0-3 independently selected from C1-C8 aliphatic groups, nitrogen, oxygen, or sulfur. 3 to 8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0 to 5 heteroatoms, or 0 to 5 independently selected from nitrogen, oxygen or sulfur Selected from 8- to 12-membered saturated, partially unsaturated, or fully unsaturated bicyclic ring systems having 5 heteroatoms; or two occurrences of R ′ are these Optionally substituted 3-12 membered saturated, moiety having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, together with the atoms to which R is attached Form monounsaturated or fully unsaturated monocyclic or bicyclic rings

  In certain other embodiments, the formula I:

Or a pharmaceutically acceptable salt thereof, wherein:
Ar ¹ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is a 5-12 membered ring. Monocyclic or bicyclic rings, aromatic rings, partially unsaturated rings, or saturated rings, as necessary, each ring independently of nitrogen, oxygen, or sulfur Containing 0 to 4 selected heteroatoms, Ar ¹ has m substituents, each substituent being independently selected from —WR ^W ;
W is a bond or an optionally substituted C ₁ -C ₆ alkylidene chain, and up to two methylene units of —CO—, —CS—, —COCO—, —CONR _{'-, - CONR'NR' -,} - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR '-, - OCONR' -, - NR'NR ', - NR 'NR'CO -, - NR'CO -, - S -, - SO, -SO 2 -, - NR' -, - SO 2 NR '-, NR'SO 2 -, - NR'SO 2 NR'- Replaced as needed and independently;
R ^W is independently R ′, halo, NO ₂ , CN, CF ₃ , or OCF ₃ ;
m is 0-5;
Each of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is independently -X-R ^X ;
X is a bond or optionally substituted C ₁ -C ₆ alkylidene chain, and up to two methylene units of —CO—, —CS—, —COCO—, —CONR′—, — _{CONR'NR '-, - CO 2 -} , - OCO -, - NR'CO 2 -, - O -, - NR'CONR' -, - OCONR '-, - NR'NR', - NR'NR'CO -, - NR'CO -, - S -, - sO, -SO 2 -, - NR '-, - sO 2 NR' -, NR 3 sO 2 -, or -NR'SO ₂ NR'- needs by Replaced accordingly and independently;
R ^X is independently R ⁵ , halo, NO ₂ , CN, CF ₃ , or OCF ₃ ;
R ⁶ is hydrogen, CF ₃ , —OR ′, —SR ′, or an optionally substituted C1-C8 aliphatic group;
R ⁷ is hydrogen or a C1-C6 aliphatic group optionally substituted with —X—R ^X ;
R ′ is independently selected from hydrogen or an optionally substituted group, which group is independently selected from C1-C8 aliphatic groups, nitrogen, oxygen, or sulfur. 0 to 5 independently selected from 3 to 8 membered saturated, partially unsaturated or fully unsaturated monocyclic rings having 1 heteroatom, or nitrogen, oxygen or sulfur Selected from 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring systems having 8 heteroatoms; or two occurrences of R ′ are these Optionally substituted 3-12 membered saturated, having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, together with the atoms to which R ′ is attached. Form a partially unsaturated or fully unsaturated monocyclic or bicyclic ring
However:
i) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen, Ar ¹ is phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methyl Phenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-hydroxyphenyl, 2,4-dinitrophenyl, phenyl 3,5-dicarboxylate But 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl, 3-nitro-4-methylphenyl, phenyl 3-carboxylate, 2-fluorophenyl, 3-fluoro Phenyl, 3-trifluoromethylphenyl, 3-ethoxyphenyl, 4-chlorophenyl, Not toxylphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl, 2-ethylphenyl or 4-ethoxycarbonylphenyl;
ii) When R ¹ , R ² , R ³ , R ⁵ , R ⁶ and R ⁷ are hydrogen and R ⁴ is methoxy, Ar ¹ is neither 2-fluorophenyl nor 3-fluorophenyl ;
iii) when R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen and R ² is 1,2,3,4-tetrahydroisoquinolin-1-yl-sulfonyl, Ar ¹ is not 3-trifluoromethylphenyl;
iv) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ are hydrogen and R ⁶ is methyl, Ar ¹ is not phenyl;
v) When R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen and R ² and R ³ together are methylenedioxy, Ar ¹ is also 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, A-carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl, 6-carboethoxy-benzothiazol-2-yl, 6-halo-benzothiazole There is no 2-yl, 6-nitro-benzothiazol-2-yl or 6-thiocyano-benzothiazol-2-yl.

vi) When R ¹ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are hydrogen and R ² and R ³ together are methylenedioxy, Ar ¹ is substituted with —SO R ^XX is 2-pyridinyl, 4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl, rather than ₂ -substituted phenyl which is ₂ NHR ^XX ;
vii) when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are hydrogen, Ar ¹ is either thiazol-2-yl or 1H-1,2,4-triazole Neither -3-yl nor 1H-1,3,4-triazol-2-yl;
viii) Ar ¹ when R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ⁷ are hydrogen and R ⁴ is CF ₃ , OMe, chloro, SCF ₃ , or OCF _3. Is 5-methyl-1,2-oxazol-3-yl, thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl, 1-methyl-1,2- (1H) -pyrazole Whether it is -5-yl, pyridin-2-yl, phenyl, N-methyl-imidazol-2-yl, imidazol-2-yl, 5-methyl-imidazol-2-yl, 1,3-oxazol-2- Neither yl nor 1,3,5- (1H) -triazol-2-yl;
ix) when each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is hydrogen, Ar ¹ is pyrimidin-2-yl or 4,6-dimethyl-pyrimidine 2-yl, 4-methoxy-6-methyl-1,3,5-triazin-2-yl; 5-bromo-pyridin-2-yl, pyridin-2-yl, 3,5-dichloro- Not pyridin-2-yl;
x) When each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ is hydrogen and R ⁶ is hydroxy, Ar ¹ is 2,6-dichloro-4-aminosulfonyl -Not phenyl;
xi) when R ² or R ³ is optionally substituted N-piperazyl, N-piperidyl, or N-morpholinyl, Ar ¹ is thiazol-2-yl, pyridyl, phenyl, thiadiazolyl, benzothiazole Rather than an optionally substituted ring selected from -2-yl or indazolyl;
xii) when R ² is optionally substituted cyclohexylamino, Ar ¹ is not optionally substituted phenyl, pyridyl or thiadiazolyl;
xiii) Ar ¹ is not an optionally substituted tetrazolyl;
xiv) when each of R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is hydrogen, and both R ¹ and R ³ are simultaneously CF ₃ , chloro, methyl, or methoxy, Ar ¹ may be 4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl, or [3,5-bis (trifluoromethyl) -1H-pyrazol-1-yl] phenyl None;
xv) When each of R ¹ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is hydrogen and Ar ¹ is thiazol-2-yl, both R ² and R ³ can be isopropyl , Not chloro or CF ₃ ;
xvi) When Ar ¹ is 4-methoxyphenyl, 4-trifluoromethylphenyl 2-fluorophenyl, phenyl, or 3-chlorophenyl:
a) when each of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is hydrogen, R ³ is not methoxy; or b) R ¹ , R ³ , R ⁴ , When each of R ⁵ , R ⁶ , and R ⁷ is hydrogen, R ² is not chloro; or c) each of R ¹ , R ² , R ³ , R ⁵ , R ⁶ , and R ⁷ When R ⁴ is hydrogen, R ⁴ is not methoxy; or d) when each of R ¹ , R ³ , R ⁴ , R ⁶ , and R ⁷ is hydrogen and R ⁵ is ethyl , R ² is not chloro;
e) when each of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is hydrogen, R ³ is not chloro;
xvi) When R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are each hydrogen and R ² is CF ₃ or OCF ₃ , Ar ¹ is [3,5 -Not bis (trifluoromethyl) -1H-pyrazol-1-yl] phenyl;
xvii) When each of R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , and R ⁷ is hydrogen and R ³ is hydrogen or CF ₃ , Ar ¹ is —OCH ₂ CH _{2 Ph,} -OCH 2 _CH 2 (2- trifluoromethyl - _{phenyl), - OCH 2 CH 2 -} (6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-yl) phenyl substituted with But not substituted 1H-pyrazol-3-yl; and xviii) the following two compounds:

Are excluded.

(2. Compounds and definitions)
The compounds of the present invention encompass the compounds generally described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.

  The term “ABC transporter” as used herein means an ABC transporter protein or fragment comprising at least one binding domain thereof, wherein the protein or fragment thereof is in vivo or in vitro. Exists. The term “binding domain” as used herein means a domain on an ABC transporter that can bind to a modulator. For example, Hwang, T .; C. J. et al. Gen. Physiol. (1998): 111 (3), 477-90.

  The term “CFTR” as used herein means a cystic fibrosis membrane conductance regulator or a mutant thereof capable of regulator activity, including ΔF508 CFTR and G551D CFTR. For example, but not limited to, see http://www.genet.sickkids.on.ca/cftr/ for CFTR mutants.

  The term “modulate” as used herein means to increase or decrease by a measurable amount.

  For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrel 1, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry, Ed. B. And March, J .; , John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

  As described herein, the compounds of the invention may optionally contain one or more substituents (eg, those generally exemplified above, or specific classes, subclasses and (Represented by the species). It will be understood that the phrase “substituted as necessary” is used interchangeably with the phrase “substituted or unsubstituted”. In general, the term “substituted” (whether preceded by the term “optionally”) replaces a hydrogen radical in a given structure with the radical of the specified substituent. Means that. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and more than one position in any given structure is selected from the specified groups 1 When more than one substituent can be substituted, the substituent can be the same or different at any position. Combinations of substituents and variables envisioned by this invention are preferably those that result, for example, in the formation of stable or chemically feasible compounds. As used herein, the term “stable” is used for their production, detection, and preferably one or more of their recovery, purification, and purposes disclosed herein. It means a compound that does not substantially change when exposed to conditions that allow it. In certain embodiments, a stable compound or a chemically feasible compound is substantially when held at a temperature of 40 ° C. or less for at least one week without moisture or other chemically reactive conditions. It will not change.

As used herein, the term “aliphatic” or “aliphatic group” refers to a straight chain (ie, unbranched) or a branched substituted or unsubstituted hydrocarbon chain (which is entirely Saturated or contains one or more unsaturated units) or monocyclic or bicyclic hydrocarbons (which are either fully saturated or contain one or more unsaturated units) Containing saturated units), but not aromatic (also referred to herein as “carbocyclic” or “cycloalkyl”), the single point of attachment to the rest of the molecule It means what you have. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. To do. In certain embodiments, “cycloaliphatic” (or “carbocyclic” or “cycloalkyl”) refers to monocyclic C ₃ -C ₈ hydrocarbons or bicyclic or tricyclic C ₈ -C _14. Means a hydrocarbon, which is fully saturated or contains one or more unsaturated units, but it is not aromatic and has a single point of attachment with the rest of the molecule Where any individual ring in the bicyclic ring system has 3 to 7 members. Suitable aliphatic groups include linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof (eg, (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (Cycloalkyl) alkenyl), but is not limited thereto. Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl (eg, decalin), bridged bicycloalkyl (eg, norbornyl or [2.2.2] bicyclo-octyl), or bridged tricyclic (eg, And adamantyl).

  As used herein, the term “heteroaliphatic” refers to an aliphatic group in which one or two carbon atoms are separately replaced with one or more of oxygen, sulfur, nitrogen, phosphorus or silicon. means. Heteroaliphatic groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and can be “heterocycle” groups, “heterocyclyl” groups, “heterocyclic aliphatic” groups or “heterocycles”. A group.

  As used herein, the term “heterocycle”, “heterocyclyl”, “heterocyclic aliphatic” or “heterocycle” is a heteroatom in which one or more ring members are independently selected. Means a non-aromatic, monocyclic, bicyclic or tricyclic ring system. In certain embodiments, the “heterocycle” group, “heterocyclyl” group, “heterocycloaliphatic” group, or “heterocycle” group has from 3 to 14 ring members, wherein one or The further ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen or phosphorus, and each ring in the system contains 3 to 7 ring members.

The term “heteroatom” refers to one or more oxygen, sulfur, nitrogen, phosphorus or silicon (any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen; Ring substitutable nitrogen (eg N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)) Meaning).

  As used herein, the term “unsaturated” means that a moiety has one or more units of unsaturation.

  As used herein, the term “alkoxy” or “thioalkyl” refers to an alkyl group attached to the carbon backbone through an oxygen atom (“alkoxy”) or a sulfur atom (“thioalkyl”) Defined).

The terms “haloaliphatic” and “haloalkoxy” refer to an aliphatic or alkoxy that may be optionally substituted with one or more halogen atoms. The term “halogen” or “halo” means F, Cl, Br or I. Examples of haloaliphatic include —CHF ₂ , —CH ₂ F, —CF ₃ , —CF ₂ —, or perhaloalkyl (eg, —CF ₂ CF ₃ ).

  The term “aryl” is used alone or as part of a larger moiety such as “aralkyl”, “aralkoxy” or “aryloxyalkyl” but has a total of 5 to 14 members Means monocyclic, bicyclic and tricyclic ring systems wherein at least one ring in the system is aromatic and each ring in the ring system is from 3 to 7 members Contains members. The term “aryl” may be used interchangeably with the term “aryl ring”. The term “aryl” also refers to heteroaryl ring systems as defined below.

  The term “heteroaryl” is used alone or as part of a larger moiety such as “heteroaralkyl” or “heteroarylalkoxy”, but has a total of 5 to 14 members Means formula, bicyclic and tricyclic ring systems, wherein at least one ring in the system is aromatic and at least one ring in the system is one or more Contains the above heteroatoms, where each ring in the system contains 3 to 7 members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) group or a heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are selected from: ^{halo; -R 0; -OR 0; -SR} 0; 1,2- methylenedioxy; 1,2 - ethylenedioxy; optionally substituted phenyl in ^{R 0} (Ph); optionally substituted with ^{R 0} -O (Ph); optionally substituted with ^{_R 0} - _{(CH 2)} ^1~ ₂ (Ph); —CH═CH (Ph) optionally substituted with R ⁰ ; —NO ₂ ; —CN; —N (R ⁰ ) ₂ ; —NR ⁰ C (O) R ⁰ ; —NR ^{0 _{C (O) N (R 0}} ) 2; -NR 0 CO 2 R 0; -NR 0 NR 0 C (O) R 0; -NR 0 NR 0 C (O) N (R 0) 2; -NR 0 _{^{NR 0 CO 2 R 0; -C}} (O) C (O) R 0; -C (O) CH 2 C (O) R 0; -CO 2 R 0 _{^{; -C (O) R 0;}} -C (O) N (R 0) 2; -OC (O) N (R 0) 2; -S (O) 2 R 0; -SO 2 N (R 0) _{^{2; -S (O) R 0}} ; -NR 0 SO 2 N (R 0) 2; -NR 0 SO 2 R 0; -C (= S) N (R 0) 2; -C (= NH) - N (R ⁰ ) ₂ ; or — (CH ₂ ) _0-2 NHC (O) R ⁰ ; where each _{occurrence of} R ⁰ is hydrogen, optionally substituted C _1-6 , unsubstituted 5 membered ˜6 membered heteroaryl or heterocycle, phenyl, —O (Ph) or —CH ₂ (Ph), or despite the above definitions, two separate occurrences of R ⁰ are the same substituent or On different substituents, together with the atoms to which each R ⁰ group is attached, forms a 3- to 8-membered cycloalkyl, aryl or heteroaryl ring, which The ring has 0 to 3 heteroatoms, which are independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group of R ⁰ are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic) or halo C _1-4 aliphatic Where each of the aforementioned C _1-4 aliphatic groups for R ⁰ is unsubstituted.

An aliphatic or heteroaliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on saturated carbons of aliphatic or heteroaliphatic groups or non-aromatic heterocycles are selected from those listed above for unsaturated carbons of aryl groups or heteroaryl groups, and further include: ^{: = O, = S, =} NNHR *, = NN (R *) 2, = NNHC (O) R *, = NNHCO 2 ( alkyl), = NNHSO ₂ (alkyl), or = a NR ^*, where Each R ^* is _{independently} selected from hydrogen or optionally substituted C _1-6 aliphatic. Optional substituents on the aliphatic group of R ^* are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halo, C _1-4 aliphatic, OH, O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic) or halo C _1-4 aliphatic Where each of the aforementioned C _1-4 aliphatic groups for R ⁰ is unsubstituted.

Optional substituents on the nitrogen of a non-aromatic heterocyclic _{^{ring, -R +, -N (R +}} ) 2, -C (O) R +, -CO 2 R +, -C (O) C (O) _{^{R +, -C (O) CH}} 2 C (O) R +, -SO 2 R +, -SO 2 N (R +) 2, -C (= S) N (R +) 2, -C (= NH) is selected from -N ^(R _{+) 2,} or ^{-NR +} _sO 2 ^R +; wherein, ^{R +} is hydrogen, _{C 1 to 6} aliphatic group optionally substituted, optionally substituted Phenyl, optionally substituted —O (Ph), optionally substituted —CH ₂ (Ph), optionally substituted — (CH ₂ ) H ₂ (Ph), optionally substituted -CH = CH (Ph); or an unsubstituted 5- to 6-membered heteroaryl or heterocycle, which has 1 to 4 heteroatoms, The number, selected from nitrogen, oxygen or sulfur), or, notwithstanding the definition above, R ⁺ existence of two separate are on the same substituent or different substituents, each R ⁺ group bonded Together with the atoms to form a 3- to 8-membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring, which has 0 to 3 heteroatoms, which are separately Independently selected from nitrogen, oxygen or sulfur. The optional substituents on the R ⁺ aliphatic group or phenyl ring are —NH ₂ , —NH (C _1-4 aliphatic), —N (C _1-4 aliphatic) ₂ , halo, C _1-4. Aliphatic, OH, O (C _1-4 aliphatic), NO ₂ , CN, CO ₂ H, CO ₂ (C _1-4 aliphatic), O (halo C _1-4 aliphatic) or halo (C _{1 ˜4} aliphatic), wherein each of the aforementioned C _1-4 aliphatic groups for R ⁺ is unsubstituted.

  The term “alkylidene chain” refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and the rest of the molecule and two points of attachment. Means having The term “spirocycloalkylidene” refers to a carbocyclic ring that may be fully saturated or have one or more unsaturated units and has two points of attachment from the same ring carbon atom to the rest of the molecule. Means.

As detailed above, in certain embodiments, R ⁰ (or R ⁺ , or other variable as defined herein), together with the atom to which each variable is attached, is a 3-membered Forms an ~ 8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl ring, which has 0 to 3 heteroatoms, which are independently selected from nitrogen, oxygen or sulfur . In a representative ring formed when two separate occurrences of R ⁰ (or R ⁺ , or other variables as defined herein) are taken together with the atoms to which each variable is attached. Includes, but is not limited to: a) two separate occurrences of R ⁰ (or R ⁺ , or other variables as defined herein) attached to the same atom, Together with the atom forms a ring, for example N (R ⁰ ) ₂ , where both occurrences of R ⁰ together with the nitrogen atom form a piperidin-1-yl group, piperazine Forms a -1-yl group or a morpholin-4-yl group; b) 2 of R ⁰ (or R ⁺ , R, R ′ or other variables as defined herein) bound to different atoms. Separate entities, together with both of these atoms, form a ring, for example If, wherein the phenyl group is substituted with two occurrences of OR ⁰ (

), These two occurrences of R ⁰ together with the oxygen atom to which they are attached form the following condensed 6-membered oxygen-containing ring:

When two separate occurrences of R ⁰ (or R ⁺ , R, R ′ or other variables similarly defined herein) are taken together with the atom to which each variable is attached, It is clear that the examples detailed above in which rings can be formed are not intended to be limiting.

  For example, attachment of substituents in a bicyclic ring system as shown below

Means that the substituent may be attached to any substitutable ring atom on any ring of the bicyclic relationship.

Unless otherwise stated, structures described herein also include all isomeric (eg, enantiomeric, diastereomeric, and geometric (ie, conformational)) forms of the structure; , R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) are meant to include conformers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric isomer (ie, conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. For example, if R ⁵ in the compound of formula I is hydrogen, the compound of formula I may exist as a tautomer:

Further, unless otherwise stated, the structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the invention are within the scope of the invention, except that hydrogen is replaced with deuterium or tritium or carbon is replaced with ¹³ C-rich carbon or ¹⁴ C rich carbon. . Such compounds are useful, for example, as analytical tools or probes in biological assays.

(3. Description of exemplary compounds)
In some embodiments of the invention, Ar ¹ is:

Wherein Ring A ₁ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Or, A ₁ and A ₂ together are an 8- to 14-membered aromatic, bicyclic or tricyclic aryl ring, wherein each of these rings is nitrogen, oxygen Or 0-4 heteroatoms independently selected from sulfur.

In some embodiments, A ₁ is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms, wherein the heteroatom is nitrogen. In some embodiments, A ₁ is optionally substituted phenyl. Or, A ₁ is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or, A ₁ is an optionally substituted pyrazinyl or triazinyl. Or, A ₁ is an optionally substituted pyridyl.

In some embodiments, A ₁ is an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, wherein the upper heteroatom is nitrogen, oxygen, or It is sulfur. In some embodiments, A ₁ is an optionally substituted 5-membered aromatic ring having 1-2 nitrogen atoms. In one embodiment, A ₁ is an optionally substituted 5-membered aromatic ring other than thiazolyl.

In some embodiments, A ₂ is an optionally substituted 6 membered aromatic ring having 0-4 heteroatoms, wherein the heteroatom is nitrogen. In some embodiments, A ₂ is optionally substituted phenyl. Or, A ₂ is an optionally substituted pyridyl, pyrimidinyl, pyrazinyl, or triazinyl.

In some embodiments, A ₂ is an optionally substituted 5-membered aromatic ring having 0-3 heteroatoms, wherein the heteroatom is nitrogen, oxygen, or sulfur. . In some embodiments, A ₂ is an optionally substituted 5 membered aromatic ring having 1-2 nitrogen atoms. In certain embodiments, A ₂ is an optionally substituted pyrrolyl.

In some embodiments, A ₂ is an optionally substituted 5-7 membered saturated or unsaturated heterocycle having 1-3 heteroatoms independently selected from nitrogen, sulfur, or oxygen. It is a cyclic ring. Exemplary such rings include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl and the like.

In some embodiments, A ₂ is an optionally substituted 5-10 membered saturated or unsaturated carbocyclic ring. In one embodiment, A ₂ is an optionally substituted 5-10 membered saturated carbocyclic ring. Exemplary such rings include cyclohexyl, cyclopentyl, and the like.

In some embodiments, Ring A ₂ has the following:

In the above formula, ring A ₂ is fused to ring A ₁ through two adjacent ring atoms.

In another embodiment, W is a bond or is a C _{1 to 6} alkylidene chain which is optionally substituted, in the C _{1 to 6} alkylidene chain, one or two methylene units are O, NR ′, S, SO, SO ₂ , or COO, CO, SO ₂ NR ′, NR′SO ₂ , C (O) NR ′, NR′C (O), OC (O), OC (O) NR 'and replaced independently as needed by, and, R ^W is, R' is or halo. In still other embodiments, each occurrence of WR ^W is independently, -C1～C3 alkyl, C1 to C3 perhaloalkyl, -O (C1 to C3 _{alkyl), - CF 3, -OCF 3} , -SCF ₃ , —F, —Cl, —Br, or—COOR ′, —COR ′, —O (CH ₂ ) ₂ N (R) (R ′), —O (CH ₂ ) N (R ′) (R ′ ), - CON (R) ( R '), - (CH 2) 2 oR', - (CH 2) oR ', monocyclic aromatic ring or bicyclic substituted optionally necessary to Optionally substituted aryl sulfone, optionally substituted 5-membered heteroaryl ring, —N (R ′) (R ′), — (CH ₂ ) ₂ N (R ′) (R ′), or - a _{(CH 2) N (RO (} R ').

  In some embodiments, m is 0. Or, m is 1. Or, m is 2. In some embodiments, m is 3. In still other embodiments, m is 4.

In one embodiment, R ⁵ is X—R ^X. In some embodiments, R ⁵ is hydrogen. Or, R ⁵ is an optionally substituted C _1-8 aliphatic group. In some embodiments, R ⁵ is optionally substituted C _1-4 aliphatic. Or, R ⁵ is benzyl.

In some embodiments, R ⁶ is hydrogen. Or, R ⁶ is an optionally substituted C _1-8 aliphatic group. In some embodiments, R ⁶ is optionally substituted C _1-4 aliphatic. In certain other embodiments, R ⁶ is — (O—C _1-4 aliphatic) or — (S—C _1-4 aliphatic). Preferably R ⁶ is —OMe or —SMe. In certain other embodiments, R ⁶ is CF ₃ .

In one embodiment of the invention, R ¹ , R ² , R ³ and R ⁴ are simultaneously hydrogen. In another embodiment, R ⁶ and R ⁷ are both hydrogen at the same time.

In another embodiment of the invention, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are simultaneously hydrogen. In another embodiment of the invention, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are simultaneously hydrogen.

In another embodiment of the invention, R ² is X—R ^X , wherein X is —SO ₂ NR′— and R ^X is R ′; that is, R ² is , _-SO 2 N (R _{') 2.} In one embodiment, the two internal R's taken together form a 5-7 membered ring optionally substituted with 0-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur. Form. Or, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are simultaneously hydrogen and R ² is SO ₂ N (R ′) ₂ .

In some embodiments, X is a bond or is a C _{1 to 6} alkylidene chain which is optionally substituted, in the C _{1 to 6} alkylidene chain, one or two non-adjacent methylene The units are optionally and independently replaced with O, NR ′, S, SO ₂ , or COO, CO, and R ^X is R ′ or halo. In still other embodiments, each occurrence of XR ^X is independently —C _1-3 alkyl, —O (C _1-3 alkyl), —CF ₃ , —OCF ₃ , —SCF ₃ , —F. , -Cl, -Br, OH, -COOR ', - COR', - O (CH 2) 2 N (R ') (R'), - O (CH 2) N (R ') (R'), -CON (R ') (R' ), - (CH 2) 2 OR ', - (CH 2) OR', phenyl optionally substituted, -N (R ') (R '), - ( _{CH 2) 2 N (R '} ) (R'), or - _{(CH 2) N (R '} ) (R').

In some embodiments, R ⁷ is hydrogen. In certain other embodiments, R ⁷ is C _1-4 straight or branched chain aliphatic.

In some embodiments, ^{R W} is selected from: halo, _{cyano, CF 3, CHF 2, OCHF} 2, Me, Et, CH (Me) 2, CHMeEt, n- propyl, t- butyl, OMe, OEt, OPh, O- fluorophenyl, O- difluorophenyl, O- methoxyphenyl, O- tolyl, O- _{benzyl, SMe, SCF 3, SCHF 2} , SEt, CH 2 CN, NH 2, NHMe, N ( _{Me) 2, NHEt, N (} Et) 2, C (O) CH 3, C (O) Ph, C (O) NH 2, SPh, SO 2 - ( amino - _{pyridyl), SO 2 NH 2, SO} 2 _{Ph, SO 2 NHPh, SO 2} -N- _morpholino, SO 2-N-pyrrolidyl, N- pyrrolyl, N- morpholino, 1-piperidyl, phenyl, benzyl, (cyclo Xyl-methylamino) methyl, 4-methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2yl, furan-2-yl, 4-methyl-4H- [1,2, 4] Triazol-3-yl, 3- (4′-chlorophenyl)-[1,2,4] oxadiazol-5-yl, NHC (O) Me, NHC (O) Et, NHC (O) Ph, NHSO ₂ Me, 2-indolyl, _{5-indolyl, -CH 2 CH 2 OH, -OCF} 3, O- (2,3- dimethylphenyl), 5-methyl-furyl, _-SO 2-N-piperidyl, 2-tolyl , 3-tolyl, 4-tolyl, O- _{butyl, NHCO 2 C (Me) 3} , CO 2 C (Me) 3, isopropenyl, n- butyl, O- _{(2,4-dichlorophenyl),} NHSO 2 PhMe, - (3-chloro-5-trifluoromethyl-2-pyridyl) phenyl-hydroxymethyl, _{2,5-dimethylpyrrolyl, NHCOCH 2 C (Me) 3} , O- (2-tert- butyl) phenyl, 2, 3-dimethylphenyl 3,4-dimethylphenyl 4-hydroxymethylphenyl, 4-dimethylaminophenyl, 2-trifluoromethylphenyl 3-trifluoromethylphenyl 4-trifluoromethylphenyl 4-cyanomethylphenyl 4-isobutylphenyl, 3. 3-pyridyl, 4-pyridyl, 4-isopropylphenyl, 3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, -Methoxyphenyl, 3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-methylthiophenyl, 4-methylthiophenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxy phenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF ₃ - phenyl, 3-trifluoromethoxy - phenyl, 4-trifluoromethoxyphenyl, 2-phenoxy Phenyl, 4-phenoxyphenyl, 2-fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl, 5-isopropyl-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl , 3-cyanophenyl, 3-chloro Phenyl, 4-chlorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluoro-phenyl 3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-isopropyloxycarbonylphenyl, 3-acetamidophenyl, 4-fluoro-3-methylphenyl 4-methanesulfinyl-phenyl, 4-methanesulfonyl-phenyl, 4-N- (2-N, N-dimethylaminoethyl) carbamoylphenyl, 5-acetyl-2 -Thienyl, 2-be Nzothienyl, 3-benzothienyl, furan-3-yl, 4-methyl-2-thienyl, 5-cyano-2-thienyl, N′-phenylcarbonyl-N-piperazinyl, —NHCO ₂ Et, —NHCO ₂ Me, N - _{pyrrolidinyl, -NHSO 2 (CH 2) 2} N- _{piperidine, -NHSO 2 (CH 2) 2} N- _{morpholine, -NHSO 2 (CH 2) 2} N (Me) 2, COCH 2 N (Me) COCH 2 NHMe , —CO ₂ Et, O-propyl, —CH ₂ CH ₂ NHCO ₂ C (Me) ₃ , hydroxy, aminomethyl, phenyl, adamantyl, cyclopentyl, ethoxyethyl, C (Me) ₂ CH ₂ OH, C (Me) _{2 CO 2 Et, -CHOHMe, CH} 2 CO 2 Et, -C (Me) 2 CH 2 NHCO 2 C (Me) ₃ , O (CH ₂ ) ₂ OEt, O (CH ₂ ) ₂ OH, CO ₂ Me, hydroxymethyl, 1-methyl-1-cyclohexyl, 1-methyl-1-cyclooctyl, 1-methyl-1-cycloheptyl , C (Et) ₂ C (Me) ₃ , C (Et) ₃ , CONHCH ₂ CH (Me) ₂ , 2-aminomethyl-phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyl, cyclohexyl, 4-methylpi _{Perijiniru, -OCO 2 Me, -C (Me} ) 2 CH 2 NHCO 2 CH 2 CH (Me) 2, -C (Me) 2 CH 2 NHCO 2 CH 2 CH 2 CH 3, C (Me) 2 CH 2 _{NHCO 2 Et, -C (Me)} 2 CH 2 NHCO 2 Me, -C (Me) 2 CH 2 NHCO 2 CH 2 C (Me) 3, -CH 2 NHCOCF 3 _{-CH 2 NHCO 2 C (Me)} 3, -C (Me) 2 CH 2 NHCO 2 (CH 2) 3 CH 3, C (Me) 2 CH 2 NHCO 2 (CH 2) 2 OMe, C (OH) ( _{CF 3) 2, -C (Me} ) 2 CH 2 NHCO 2 CH 2 - _{tetrahydrofuran-3-yl, C (Me) 2 CH 2} O (CH 2) 2 OMe or 3-ethyl-2,6-dioxo, Piperidin-3-yl.

  In one embodiment, R 'is hydrogen.

In one embodiment, R ′ is a C1-C8 aliphatic group optionally substituted with up to three substituents selected from halo, CN, CF ₃ , CHF ₂ , OCF ₃ or OCHF _2. There, wherein up to two methylene units of the C1~C8 aliphatic optionally, -CO -, - CONH (C1~C4 _{alkyl) -, - CO 2 -,} - OCO -, - N (C1 -C4 _{alkyl) CO 2 -, - O -} , - N (C1~C4 alkyl) CON (C1 -C4 alkyl) -, - OCON (C1~C4 alkyl) -, - N (C1~C4 alkyl) CO -, - S -, - N (C1~C4 _{alkyl) -, - SO 2 N (} C1~C4 alkyl) -, N (C1~C4 alkyl) SO ₂ -, or -N (C1 -C4 alkyl) SO ₂ N (C1-C4 alkyl)- It is replaced.

In one embodiment, R ′ is 3-8 membered saturated, partially unsaturated, or fully unsaturated having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. A monocyclic ring, wherein R ′ is optionally substituted with up to three substituents selected from halo, CN, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ or C1-C6 alkyl. It is, where up to two methylene units of the C1~C6 alkyl is optionally, -CO -, - CONH (C1~C4 _{alkyl) -, - CO 2 -,} - OCO -, - N (C1 -C4 _{alkyl) CO 2 -, - O -} , - N (C1~C4 alkyl) CON (C1 -C4 alkyl) -, - OCON (C1~C4 alkyl) -, - N (C1~C4 alkyl) CO-, -S-, -N (C1-C4 _{Alkyl) -, - SO 2 N (} C1~C4 alkyl) -, N (C1 -C4 alkyl) SO ₂ -, or -N (C1 -C4 _alkyl) SO 2 N (C1 -C4 alkyl) - in is replaced.

In one embodiment, R ′ is an 8-12 membered saturated, partially unsaturated or fully having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. An unsaturated bicyclic ring system; wherein R ′ is optionally up to 3 substituents selected from halo, CN, CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ or C1-C6 alkyl depending being substituted, wherein up to two methylene units of the C1~C6 alkyl is optionally, -CO -, - CONH (C1~C4 _{alkyl) -, - CO 2 -,} - OCO -, - N (C1~C4 _{alkyl) CO 2 -, - O -} , - N (C1~C4 alkyl) CON (C1 -C4 alkyl) -, - OCON (C1~C4 alkyl) -, - N (C1~ C4 alkyl) CO-, -S-, -N ( C1 -C4 _{alkyl) -, - SO 2 N (} C1~C4 alkyl) -, N (C1 -C4 alkyl) SO ₂ -, or -N (C1 -C4 _alkyl) SO 2 N (C1 -C4 alkyl) - in Replaced.

In one embodiment, the two occurrences of R ′ must have 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, together with the atoms to which they are attached. To form a 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring, depending on where R ′ is halo, CN , CF ₃ , CHF ₂ , OCF ₃ , OCHF ₂ or up to 3 substituents selected from C 1 -C 6 alkyl, optionally substituted up to 2 of the above C 1 -C 6 alkyl methylene units are optionally, -CO -, - CONH (C1~C4 _{alkyl) -, - CO 2 -,} - OCO -, - N (C1~C4 _{alkyl) CO 2 -, - O -} , - N (C1-C4 alkyl) CON (C1-C4 alkyl) ) -, - OCON (C1 -C4 alkyl) -, - N (C1 -C4 alkyl) CO -, - S -, - N (C1 -C4 alkyl) _-, - SO 2 N (C1 -C4 alkyl) -, N (C1 -C4 alkyl) SO ₂ -, or -N (C1 -C4 _alkyl) SO 2 N (C1 -C4 alkyl) - in is replaced.

  According to one embodiment, the present invention provides compounds of formula IIA or formula IIB:

Of the compound.

  According to another embodiment, the present invention provides compounds of formula IIIA, formula IIIB, formula IIIC, formula IIID or formula IIIE:

Wherein each of X ₁ , X ₂ , X ₃ , X ₄ and X ₅ is independently selected from CH or N; and X ₆ is O, S or NR ′ It is.

In one embodiment, compounds of formula IIIA, formula IIIB, formula IIIC, formula IIID, or formula IIIE have y occurrences of substituents X—R ^X , where y is 0-4. . Or, y is 1. Or, y is 2.

In some embodiments of Formula IIIA, X ₁ , X ₂ , X ₃ , X _4, and X ₅ are optionally substituted phenyl, together with WR ^W and m.

In some embodiments of Formula IIIA, X ₁ , X ₂ , X ₃ , X ₄ and X ₅ are taken together to form the following:

An optionally substituted ring selected from more.

In some embodiments of Formula IIIB, Formula IIIC, Formula IIID, or Formula IIIE, X ₁ , X ₂ , X ₃ , X ₄ , X _5, or X ₆ together with Ring A ₂ is selected from Is an optionally substituted ring:

In some embodiments, R ^W is halo, cyano, CF ₃ , CHF ₂ , OCHF ₂ , Me, Et, CH (Me) ₂ , CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh, Oh. - fluorophenyl, O- difluorophenyl, O- methoxyphenyl, O- tolyl, O- _{benzyl, SMe, SCF 3, SCHF 2} , SEt, CH 2 CN, NH 2, NHMe, N (Me) 2, NHEt, N _{(Et) 2, C (O} ) CH 3, C (O) Ph, C (O) NH 2, SPh, SO 2 - ( amino - _{pyridyl), SO 2 NH 2, SO} 2 Ph, SO 2 NHPh, SO _{2-N-morpholino,} SO 2-N-pyrrolidyl, N- pyrrolyl, N- morpholino, 1-piperidyl, phenyl, benzyl, (cyclohexyl - methylamino Methyl, 4-methyl-2,4-dihydro-pyrazol-3-on-2-yl, benzimidazol-2yl, furan-2-yl, 4-methyl-4H- [1,2,4] triazole-3 - yl, 3- (4'-chlorophenyl) - [1,2,4] oxadiazol-5-yl selection, NHC (O) Me, NHC (O) Et, from NHC (O) Ph or NHSO ₂ Me Is done.

In some embodiments, X and ^{R X,} taken together, Me, Et, _{halo, CN, CF 3, OH,} OMe, OEt, SO 2 N (Me) ( fluorophenyl), _SO 2 - ( piperidin-1-yl or _SO 2-N-pyrrolidinyl - 4-methyl.

  According to another embodiment, the present invention provides compounds of formula IVA, formula IVB or formula IVC:

Of the compound.

In one embodiment, compounds of formula IVA, formula IVB, and formula IVC have y occurrences of substituents X—R ^X , where y is 0-4. Or, y is 1. Or, y is 2.

In one embodiment, the present invention provides compounds of formula IVA, formula IVB, and formula IVC, wherein X is a bond and R ^X is hydrogen.

In one embodiment, the invention provides compounds of formula IVA, formula IVB, and formula IVC, wherein ring A ₂ is required with 0-3 heteroatoms selected from O, S, or N Saturated, unsaturated, or aromatic seven-membered ring, depending on Exemplary rings include azepanyl, 5,5-dimethylazepanyl, and the like.

In one embodiment, the invention provides compounds of Formula IVB and Formula IVC, wherein Ring A ₂ is optionally 0-3 heteroatoms selected from O, S, or N. It is a substituted, saturated, unsaturated, or aromatic 6-membered ring. Exemplary rings include piperidinyl, 4,4-dimethylpiperidinyl and the like.

In one embodiment, the invention provides compounds of Formula IVB and Formula IVC, wherein Ring A ₂ is optionally 0-3 heteroatoms selected from O, S, or N. It is a substituted, saturated, unsaturated or aromatic 5-membered ring.

In one embodiment, the invention provides compounds of Formula IVB and Formula IVC, wherein Ring A ₂ is a 5-membered ring optionally substituted with 1 carbon atom (eg, pyrrolyl or Pyrrolidinyl).

  According to one embodiment of Formula IVA, the following Formula VA-1:

Wherein each of WR ^W2 and WR ^W4 is independently hydrogen, CN, CF ₃ , halo, C1-C6 linear or branched alkyl, 3-12 membered cyclic fat Selected from the group, phenyl, C5-C10 heteroaryl or C3-C7 heterocyclic, wherein said heteroaryl or heterocyclic has up to 3 heteroatoms selected from O, S or N wherein the ^{WR W2} and ^{WR W4} _{are, -OR ', - CF 3,} -OCF 3, SR', S (O) R ', SO 2 R', - SCF 3, halo, CN, -COOR ' , —COR ′, —O (CH ₂ ) ₂ N (R ′) (R ′), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′) (R ′), — _{(CH 2) 2 OR ',} - (CH 2) OR', CH 2 CN, optionally substituted Fe Le or phenoxy, -N (R ') (R '), - NR'C (O) OR ', - NR'C (O) R', - (CH 2) 2 N (R ') (R') Or independently and optionally substituted with up to three substituents selected from — (CH ₂ ) N (R ′) (R ′); and WR ^W5 is hydrogen, —OH , NH ₂ , CN, CHF ₂ , NHR ′, N (R ′) ₂ , —NHC (O) R ′, —NHC (O) OR ′, NHSO ₂ R ′, —OR ′, CH ₂ OH, CH ₂ Selected from N (R ′) ₂ , C (O) OR ′, SO ₂ NHR ′, SO ₂ N (R ′) ₂ or CH ₂ NHC (O) OR ′. Or, WR ^W4 and WR ^W5 are taken together to form a 5-7 membered ring containing 0-3 heteroatoms selected from N, O or S, wherein 3 Optionally substituted with up to WR ^W substituents.

In one embodiment, compounds of formula VA-1 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0.

In one embodiment, the present invention provides a compound of formula VA-1, wherein X is a bond and R ^X is hydrogen.

In one embodiment, the present invention provides a compound of formula VA-1, wherein:
Each of WR ^W2 and WR ^W4 is independently selected from hydrogen, CN, CF ₃ , halo, C1-C6 linear or branched alkyl, 3-12 membered cyclic aliphatic or phenyl, wherein the ^{WR W2} and ^{WR W4} _{are, -OR ', - CF 3,} -OCF 3, -SCF 3, halo, -COOR', - COR ', - O (CH 2) 2 N (R') (R ' ), —O (CH ₂ ) N (R ′) (R ′), —CON (R ′) (R ′), — (CH ₂ ) ₂ OR ′, — (CH ₂ ) OR ′, as necessary Substituted phenyl, —N (R ′) (R ′), —NC (O) OR ′, —NC (O) R ′, — (CH ₂ ) ₂ N (R ′) (R ′) or — ( _{CH 2) N (R ')} (R' independently substituents from) up to three substituents selected, and are optionally substituted; and WR ^W5 is hydrogen, _{OH, NH 2, CN, NHR} ', N (R') 2, -NHC (O) R ', - NHC (O) OR', NHSO 2 R ', - OR', CH 2 OH, C (O) Selected from OR ′, SO ₂ NHR ′ or CH ₂ NHC (O) O— (R ′).

In one embodiment, the present invention provides a compound of formula VA-1, wherein:
WR ^W2 represents —OR ′, —CF ₃ , —OCF ₃ , SR ′, S (O) R ′, SO ₂ R ′, —SCF ₃ , halo, CN, —COOR ′, —COR ′, —O ( _{CH 2) 2 N (R '} ) (R'), - O (CH 2) N (R ') (R'), - CON (R ') (R'), - (CH 2) 2 OR ', _{- (CH 2) oR ',} CH 2 CN, optionally substituted phenyl or phenoxy, -N (R') (R '), - NR'C (O) oR', - NR'C (O ) R ′, — (CH ₂ ) ₂ N (R ′) (R ′) or — (CH ₂ ) N (R ′) (R ′) optionally substituted with three substituents. A phenyl ring;
WR ^W4 is C1-C6 linear or branched alkyl; and WR ^W5 is OH.

In one embodiment, each of WR ^W2 and WR ^W4 is independently selected from CF ₃ or halo. In one embodiment, each of WR ^W2 and WR ^W4 is independently selected from optionally substituted hydrogen, C1-C6 linear or branched alkyl. In certain embodiments, each of WR ^W2 and WR ^W4 is independently an optionally substituted n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethyl- Selected from 2-hydroxyethyl, 1,1-dimethyl-2- (ethoxycarbonyl) -ethyl, 1,1-dimethyl-3- (t-butoxycarbonyl-amino) propyl or n-pentyl.

In one embodiment, each of WR ^W2 and WR ^W4 is independently selected from an optionally substituted 3-12 membered cycloaliphatic. Illustrative embodiments of such cycloaliphatics include cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, [2.2.2. ] Bicyclo-octyl, [2.3.1. Bicyclo-octyl or [3.3.1] bicyclo-nonyl.

In certain embodiments, WR ^W2 is hydrogen and WR ^W4 is C1-C6 straight or branched alkyl. In certain embodiments, WR ^W4 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl or t-butyl.

In certain embodiments, WR ^W4 is hydrogen and WR ^W2 is C1-C6 straight or branched alkyl. In certain embodiments, WR ^W2 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl or n-pentyl.

In certain embodiments, each of WR ^W2 and WR ^W4 is C1-C6 linear or branched alkyl. In certain embodiments, each of WR ^W2 and WR ^W4 is selected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl or pentyl.

In one embodiment, ^{WR W5} is _{hydrogen, CHF 2, NH 2, CN} , NHR ', N (R') 2, CH 2 N (R ') 2, -NHC (O) R', - NHC ( O) oR ', - oR' , it is selected from C (O) oR 'or _SO 2 NHR'. Or, WR ^W5 is —OR ′ (eg, OH).

In certain embodiments, ^{WR W5} is _{hydrogen, NH 2, CN, CHF 2} , NH (C1~C6 alkyl), N (C1 -C6 _{alkyl) 2, -NHC (O) (} C1~C6 alkyl), - _{CH 2 NHC (O) O (} C1~C6 alkyl), - NHC (O) O (C1~C6 alkyl), - OH, -O (C1~C6 alkyl), C (O) O ( C1~C6 alkyl) It is selected from _CH 2 O (C1 -C6 alkyl) or _SO 2 NH _2. In another ^embodiment, WR W5 _{is, -OH, OMe, NH 2,} -NHMe, -N (Me) 2, -CH 2 NH 2, CH 2 OH, NHC (O) OMe, NHC (O) OEt, _{CN, CHF 2, -CH 2 NHC} (O) O (t- butyl), - O-(ethoxyethyl), - O-(hydroxyethyl) - is selected from C (O) OMe or _-SO 2 NH ₂ The

In one embodiment, the compound of formula VA-1 has one, preferably more, or more preferably all of the following features:
i) WR ^W2 is hydrogen;
ii) ^{WR W4} is an alkyl or monocyclic aliphatic or bicyclic aliphatic C1~C6 straight or branched chain; and iii) ^{WR W5} is _{hydrogen, CN, CHF 2, NH 2} , NH (C1 -C6 alkyl), N (C1 -C6 _{alkyl) 2, -NHC (O) (} C1~C6 alkyl), - NHC (O) O (C1~C6 _{alkyl), - CH 2 C (O} ) O ( C1 -C6 alkyl), - OH, -O (C1 -C6 alkyl), is selected from C (O) O (C1~C6 alkyl) or _SO 2 NH _2.

In one embodiment, the compound of formula VA-1 has the following characteristics:
i) ^{WR W2} is halo, C1 -C6 _alkyl, CF 3, CN, or C1 -C4 alkyl, -O (C1 -C4 alkyl), or optionally by a substituent from halo up to three substituents selected Be substituted phenyl;
ii) ^{WR W4} is, CF _3, halo, C1 -C6 alkyl or C6~C10 be cyclic aliphatic; and iii) ^{WR W5} _{is, OH, NH 2, NH (} C1~C6 alkyl), or N ( C1-C6 alkyl),
One, preferably more, or more preferably all.

In one embodiment, X—R ^X is at the 6-position of the quinolinyl ring. In certain embodiments, X—R ^{X taken} together is C 1 -C 6 alkyl, —O— (C 1 -C 6 alkyl) or halo.

In one embodiment, X—R ^X is at the 5-position of the quinolinyl ring. In certain embodiments, X—R taken together is —OH.

In another embodiment, the invention provides that WR ^W4 and WR ^{W5 taken} together form a 5-7 membered ring comprising 0-3 heteroatoms selected from N, O, or S. , Wherein the ring provides a compound of formula VA-1, optionally substituted with up to 3 WR ^W substituents.

In certain embodiments, WR ^W4 and WR ^W5 are taken together to form an optionally substituted 5-7 membered saturated, unsaturated or aromatic ring containing 0 heteroatoms. . In other embodiments, WR ^W4 and WR ^{W5 taken} together are an optionally substituted 5-7 membered ring comprising 1-3 heteroatoms selected from N, O, or S. Form. In certain other embodiments, WR ^W4 and WR ^{W5 taken} together comprise an optionally substituted saturated, unsaturated, or aromatic containing one heteroatom. , Form a 5- to 7-membered ring. In certain other embodiments, WR ^W4 and WR ^W5 are taken together to form an optionally substituted 5-7 membered ring containing one oxygen heteroatom.

  In another embodiment, the present invention provides compounds of formula VA-2:

Provide the compound here:
Y is CH ₂ , C (O) O, C (O), or S (O) ₂ ;
m is 0-4; and X, R ^X , W, and R ^W are as defined above.

In one embodiment, compounds of formula VA-2 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

In one embodiment, Y is C (O). In another embodiment, Y is C (O) O. Or, Y is S (O) ₂ . Or, Y is CH _2.

  In one embodiment, m is 1 or 2. Or, m is 1. Or, m is 0.

  In one embodiment, W is a bond.

In another embodiment, ^{R W} is, C1 -C6 aliphatic, halo, CF _3, or C1 -C6 alkyl, halo, cyano, or phenyl which is optionally substituted with CF _3, where the C1~C6 up to two methylene units of the aliphatic or C1~C6 _{alkyl, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR 'CONR' -, - OCONR ' -, - NR'CO -, - S -, - NR' -, - sO 2 NR '-, NR'SO 2 -, or -NR'SO ₂ NR'- needs in Replaced accordingly. In another embodiment, R ′ is C1-C4 alkyl. Exemplary embodiments of WR ^W include methyl, ethyl, propyl, tert-butyl, or 2-ethoxyphenyl.

In another embodiment, ^{R W} in ^{Y-R W} is "a C1~C6 aliphatic optionally substituted with _2, where R N _(R)" is hydrogen, in C1~C6 alkyl Or two R ″ together form a 5-7 membered heterocyclic ring having up to two additional heteroatoms selected from O, S, or NR ′. Typical such heterocyclic rings include pyrrolidinyl, piperidinyl, morpholinyl, or thiomorpholinyl.

  In another embodiment, the present invention provides compounds of formula VA-3:

Provide the compound here:
Q is W;
R ^Q is an ^{R W;}
m is 0-4;
n is 0-4; and X, R ^X , W, and R ^W are as defined above.

In one embodiment, compounds of formula VA-3 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

  In one embodiment, n is 0-2.

  In another embodiment, m is 0-2. In one embodiment, m is 0. In one embodiment, m is 1. Or, m is 2.

In one embodiment, QR ^Q together, _{halo, CF 3, OCF 3, CN} , C1~C6 aliphatic, O-C1 -C6 aliphatic, O- phenyl, NH (C1 -C6 aliphatic ), Or N (C 1 -C 6 aliphatic) ₂ , wherein the aliphatic and phenyl are optionally substituted with up to 3 substituents, wherein the substituents are C 1 -C 6 alkyl, O— C1~C6 alkyl, halo, cyano, OH, or from CF _3, wherein up to two methylene units of the C1~C6 aliphatic or C1~C6 alkyl, -CO -, - CONR '- , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, SOR', SO 2 R _{', -SO 2 NR' -,} NR'SO 2 - or -NR'S, Optionally replaced with ₂ NR'-. In another embodiment, R ′ is C1-C4 alkyl.

Exemplary QR ^Q, methyl, isopropyl, sec- butyl, _{hydroxymethyl, CF 3, NMe 2, CN} , CH 2 CN, fluoro, _{chloro, OEt, OMe, SMe, OCF} 3, OPh, C (O) OMe, C (O) O-iPr, S (O) Me, NHC (O) Me, or S (O) ₂ Me.

  In another embodiment, the present invention provides compounds of formula VA-4:

Wherein ^X , R ^X , and R ^W are as defined above.

In one embodiment, compounds of formula VA-4 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

In one embodiment, ^{R W} is Cl -C 12 aliphatic, C5-C10 cycloaliphatic, or a C5~C7 heterocyclic ring, the aliphatic, cycloaliphatic or heterocyclic ring, is 3 Optionally substituted with up to 1 substituent, which substituent is selected from C1-C6 alkyl, halo, cyano, oxo, OH, or CF ₃ , wherein the C1-C6 aliphatic or C1-C6 up to two methylene units of the alkyl _{are, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR' -, - OCONR'- , -NR'CO -, - S -, - NR '-, - sO 2 NR' -, NR'SO 2 -, or optionally replaced with -NR'SO ₂ NR'-. In another embodiment, R ′ is C1-C4 alkyl.

Exemplary ^{R W,} methyl, ethyl, n-propyl, isopropyl, n- butyl, sec- butyl, t- butyl, n- pentyl, vinyl, cyanomethyl, hydroxymethyl, hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl Or —C (CH ₃ ) ₂ —NHC (O) OT, where T is C1-C4 alkyl, methoxyethyl, or tetrahydrofuranylmethyl.

  In another embodiment, the present invention provides compounds of formula VA-5:

Provide the compound here:
m is 0 to 4; and X, R ^X , W, R ^W , and R ′ are as defined above.

In one embodiment, compounds of formula VA-5 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

  In one embodiment, m is 0-2. Or, m is 1. Or, m is 2.

  In another embodiment, both R 'are hydrogen or one R' is hydrogen and the other R 'is C1-C4 alkyl (eg, methyl). Or, both R 'are C1-C4 alkyl (eg, methyl).

In another embodiment, m is 1 or 2 and, ^{R W} is _halo, CF 3, CN, C1 -C6 aliphatic, O-C1 -C6 aliphatic or phenyl, the aliphatic and phenyl are optionally substituted with up to three substituents, the substituents are C1 -C6 alkyl, O-C1 -C6 alkyl are selected from halo, cyano, OH, or from CF _3, the C1 ~C6 up to two methylene units of the aliphatic or C1~C6 _{alkyl, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR' CONR '-, - OCONR' - , - NR'CO -, - S -, - NR '-, - sO 2 NR' -, NR'SO 2 -, or optionally with -NR'SO ₂ NR'- Replaced. In another embodiment, R ′ is C1-C4 alkyl.

Exemplary embodiments of R ^W is _chloro, CF 3, OCF _3, methyl, ethyl, n-propyl, isopropyl, n- butyl, t- butyl, methoxy, ethoxy, propyloxy or 2-ethoxy phenyl, Can be mentioned.

  In another embodiment, the present invention provides compounds of formula VA-6:

Provide the compound here:
Ring B is optionally substituted with occurrences of up to the n -Q-R ^Q, 5- to 7-membered, monocyclic or bicyclic, be a heterocyclic ring or heteroaryl ring Where n is 0 to 4 and Q and R ^Q are as defined above; and Q, R ^Q , X, R ^X , W, and R ^W are as defined above That's right.

  In one embodiment, compounds of formula VA-6 have y occurrences of X-R, wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

  In one embodiment, m is 0-2. Or, m is 0. Or, m is 1.

  In one embodiment, n is 0-2. Or is 0. Or, n is 1.

In another embodiment, ring B is optionally substituted with occurrences of up to the n -Q-R ^Q, with heteroatoms of O, up to 2 groups selected from S or N, 5 It is a ˜7-membered monocyclic heterocyclic ring. Exemplary heterocyclic rings include N-morpholinyl, N-piperidinyl, 4-benzoyl-piperazin-1-yl, pyrrolidin-1-yl, or 4-methyl-piperidin-1-yl.

In another embodiment, ring B is optionally substituted with occurrences of up to the n -Q-R ^Q, with heteroatoms of O, up to 2 groups selected from S or N, 5 A 6-membered monocyclic heteroaryl ring. Exemplary such rings include benzimidazol 2-yl, 5-methyl-furan-2-yl, 2,5-dimethyl-pyrrol-1-yl, pyridin-4-yl, indol-5-yl, Indol-2-yl, 2,4-dimethoxy-pyrimidin-5-yl, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl, benzothiophen-2-yl, 4-methyl -Thien-2-yl, 5-cyano-thien-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl.

  In another embodiment, the present invention provides compounds of formula V-B-1:

Provide the compound here:
One of Q ₁ and Q ₃ is N (WR ^W ) and the other of Q ₁ and Q ₃ is selected from O, S or N (WR ^W );
Q ₂ is C (O), CH ₂ —C (O), C (O) —CH ₂ , CH ₂ , CH ₂ —CH ₂ , CF ₂ , or CF ₂ —CF ₂ ;
m is 0-3; and X, W, R ^X , and R ^W are as defined above.

In one embodiment, compounds of formula VB-1 have y occurrences of X—R ^X , where y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

In one embodiment, Q ₃ is N (WR ^W ); exemplary WR ^W includes hydrogen, C1-C6 aliphatic, C (O) C1-C6 aliphatic, or C (O) OC1. -C6 aliphatic is mentioned.

In another embodiment, Q ₃ is N (WR ^W ), Q ₂ is C (O), CH ₂ , CH ₂ —CH ₂ , and Q ₁ is O.

  In another embodiment, the present invention provides compounds of formula VB-2:

Provide the compound here:
R ^W1 is hydrogen or C1-C6 aliphatic;
Each of R ^W3 is hydrogen or C1-C6 aliphatic; or both R ^W3 together have up to two heteroatoms selected from O, S or NR ′, Forming a C6 cycloalkylalkyl or heterocyclic ring, said ring optionally substituted with up to 2 WR ^W substituents;
m is 0-4; and X, R ^X , W, and R ^W are as defined above.

In one embodiment, compounds of formula VB-2 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

In one embodiment, WR ^W1 is hydrogen, C1-C6 aliphatic, C (O) C1-C6 aliphatic, or C (O) OC1-C6 aliphatic.

In another embodiment, each R ^W3 is hydrogen, C1-C4 alkyl. Or, both R ^W3 together represent a C3-C6 cycloaliphatic ring or a 5-7 membered heterocyclic ring having up to 2 heteroatoms selected from O, S or N. Wherein the cycloaliphatic or heterocyclic ring is optionally substituted with up to three substituents selected from WR ^W1 . Exemplary such rings include cyclopropyl, cyclopentyl, optionally substituted piperidinyl, and the like.

  In another embodiment, the present invention provides compounds of formula VB-3:

Provide the compound here:
Q ₄ is a bond, C (O), C (O) O, or S (O) ₂ ;
R ^W1 is hydrogen or C1-C6 aliphatic;
m is 0-4; and X, W, R ^W , and R ^X are as defined above.

In one embodiment, compounds of formula VB-3 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0.

In one embodiment, Q ₄ is C (O). Or _{Q 4} are a C (O) O. In another embodiment, R ^W1 is C1-C6 alkyl. Exemplary ^RW1 includes methyl, ethyl, or t-butyl.

  In another embodiment, the present invention provides compounds of formula VB-4:

Provide the compound here:
m is 0-4; and X, R ^X , W, and R ^W are as defined above.

In one embodiment, compounds of formula VB-4 have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

  In one embodiment, m is 0-2. Or, m is 0. Or, m is 1.

  In another embodiment, the cycloaliphatic ring is a 5-membered ring. Alternatively, the ring is a 6-membered ring.

  In another embodiment, the present invention provides compounds of formula VB-5:

Provide the compound here:
Ring A ₂ is phenyl or a 5-6 membered heteroaryl ring, wherein ring A ₂ and phenyl fused to ring A ₂ have up to 4 substituents The group is independently selected from WR ^W ;
m is 0-4; and X, W, R ^W and R ^X are as defined above.

In one embodiment, compounds of formula VB-5 have y occurrences of X—R ^X , where y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, y is 2.

In one embodiment, ring A ₂ is pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, selected oxadiazolyl or triazolyl, a 5-membered ring which is optionally substituted.

In one embodiment, ring A ₂ is pyrrolyl, pyrazolyl, thiadiazolyl, imidazolyl, oxazolyl, is selected from triazolyl, a 5-membered ring which is optionally substituted. Exemplary such rings are:

And the ring is optionally substituted as described above.

In another embodiment, ring A ₂ is a 6-membered ring which is optionally substituted. Exemplary such rings include pyridyl, pyrazinyl, or triazinyl. In another embodiment, the ring is optionally pyridyl.

In one embodiment, ring A ₂ is phenyl.

In another embodiment, ring A ₂ is pyrrolyl, pyrazolyl, pyridyl, or thiadiazolyl.

  Exemplary W in formula VB-5 includes a bond, C (O), C (O) O, or C1-C6 alkylene.

Exemplary ^{R W} in formula V-B-5, cyano, halo, C1 -C6 aliphatic, C3 -C6 cycloaliphatic, aryl, O, and Up to two heteroatoms selected from S or N The aliphatic, phenyl, and heterocyclic groups are optionally and independently substituted with up to 3 substituents, the substituents being C1- C6 alkyl, O-C1 -C6 alkyl, halo, cyano, OH, or from CF _3, wherein up to two methylene units of said C1 -C6 aliphatic or C1 -C6 alkyl, -CO -, - CONR ' _{-, - CO 2 -, -} OCO -, - NR'CO 2 -, - O -, - NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, - _{SO 2 NR '-, NR'SO 2} -, or -NR'SO ₂ NR' In are replaced, if necessary. In another embodiment, R ′ is C1-C4 alkyl.

  In one embodiment, the present invention provides compounds of formula VB-5-a:

Provide the compound here:
G ₄ is hydrogen, halo, CN, CF ₃ , CHF ₂ , CH ₂ F, optionally substituted C 1 -C 6 aliphatic, aryl-C 1 -C 6 alkyl, or phenyl, where G ₄ is optionally substituted with WR ^W substituents up to four; wherein up to two methylene units of the C1~C6 aliphatic or C1~C6 alkyl, -CO -, - CONR '- , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, - SO 2 NR'- , NR′SO ₂ —, or —NR′SO ₂ NR′— as needed;
G ₅ is hydrogen or C1~C6 aliphatic optionally substituted; indole ring system is optionally substituted further required in up to three substituents selected from WR ^W.

In one embodiment, compounds of formula VB-5-a have y occurrences of X—R ^X , wherein y is 0-4. In one embodiment, y is O. Or, y is 1. Or, y is 2.

In one embodiment, G ₄ is hydrogen. Or, G ₅ is hydrogen.

In another embodiment, G ₄ is hydrogen and G ₅ is C 1 -C 6 aliphatic, the aliphatic optionally substituted with C 1 -C 6 alkyl, halo, cyano, or CF _3. is, and up to two methylene units of the C1~C6 aliphatic or C1~C6 _{alkyl, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, - SO 2 NR' -, NR'SO 2 -, or -NR'SO ₂ NR ' -Replaced as necessary. In another embodiment, R ′ is C1-C4 alkyl.

In another embodiment, G ₄ is hydrogen and G ₅ is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH ₂ C (O). _OMe, a _{(CH 2) 2 -NHC (O} ) O-tert- butyl or cyclopentyl.

In another embodiment, G ₅ is hydrogen and G ₄ is halo, C 1 -C 6 aliphatic or phenyl, and the aliphatic or phenyl is C 1 -C 6 alkyl, halo, cyano, or CF ₃ in optionally substituted up to two methylene units of the C1~C6 aliphatic or C1~C6 _{alkyl, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO _{2 -, - O -, -} NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, - SO 2 NR' -, NR'SO 2 -, or -NR Replaced with 'SO ₂ NR'- as necessary. In another embodiment, R ′ is C1-C4 alkyl.

In another embodiment, G ₅ is hydrogen and G ₄ is halo, CF ₃ , ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, (4-C (O) NH ( CH _{2) 2} -NMe ₂₎ - phenyl, 2-methoxy-4-chloro - phenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec- butylaminocarbonyl, ethyl, t- butyl Or piperidin-1-ylcarbonyl.

In another embodiment, G ₄ and G ₅ are both hydrogen, and the nitrogen ring atom of the indole ring is substituted with C1-C6 aliphatic, C (O) (C1-C6 aliphatic), or benzyl. are, the aliphatic or benzyl, C1 -C6 alkyl, halo, cyano, or optionally substituted with CF _3, wherein up to two methylene units of said C1 -C6 aliphatic or C1 -C6 alkyl _{, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR' -, - OCONR '-, - NR'CO -, - S -, - NR '-, - sO 2 NR' -, NR'SO 2 -, or optionally replaced with -NR'SO ₂ NR'-. In another embodiment, R ′ is C1-C4 alkyl.

In another embodiment, G ₄ and G ₅ are both hydrogen, and the nitrogen ring atom of the indole ring is acyl, benzyl, C (O) CH ₂ N (Me) C (O) CH ₂ NHMe, Or substituted with ethoxycarbonyl.

  In another embodiment, the present invention provides compounds of formula I ':

Or a pharmaceutically acceptable salt thereof,
Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and Ar ¹ are as defined above for compounds of formula I ′.

In one embodiment, each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and Ar ¹ in the compound of formula I ′ is independently a compound of formula I The form is as defined above for either.

  Representative compounds of the present invention are shown in Table 1 below.

  (Table 1)

In another embodiment, the present invention provides compounds useful as intermediates in the synthesis of compounds of formula I. In one embodiment, such compounds have the formula AI:

Or a salt thereof; where:
G ₁ is hydrogen, R ′, C (O) R ′, C (S) R ′, S (O) R ′, S (O) ₂ R ′, Si (CH ₃ ) ₂ R ′, P (O ) (OR ′) ₃ , P (S) (OR ′) ₃ , or B (OR ′) ₂ ;
G ₂ is halo, CN, CF _3, an isopropyl or phenyl, where the isopropyl or phenyl is optionally substituted with up to three substituents selected from WR ^W, wherein In which W and R ^W are as defined above for Formula I and embodiments thereof;
G ₃ is isopropyl or a C3-C10 cycloaliphatic ring, wherein G ₃ is optionally substituted with up to three substituents selected from WR ^W , wherein W 3 and R ^W are as defined above for formula I and embodiments thereof;
However, when G ₁ is methoxy and G ₃ is tert-butyl, G ₂ is not 2-amino-4-methoxy-5-tert-butyl-phenyl.

In one embodiment, the present invention provides a compound of formula A-I, provided that when G ₂ and G ₃ are each t- butyl, G ₁ is not hydrogen.

In another embodiment:
G ₁ is hydrogen;
G ₂ is halo or isopropyl, wherein the isopropyl is optionally substituted with up to 3 substituents selected from R ′; and G ₃ is isopropyl or C3-C10 cyclic An aliphatic ring wherein G ₃ is optionally substituted with up to three substituents selected from R ′;

In another embodiment:
G ₁ is hydrogen;
G ₂ is halo, preferably fluoro; and G ₃ is a C3-C10 cycloaliphatic ring, where G ₃ is selected from methyl, ethyl, propyl, or butyl Optionally substituted with up to a maximum of substituents.

In another embodiment:
G ₁ is hydrogen;
G ₂ is CN, halo, or CF ₃ ; and G ₃ is isopropyl or a C3-C10 cycloaliphatic ring, wherein G ₃ is up to 3 substitutions selected from R ′ Optionally substituted with a group.

In another embodiment:
G ₁ is hydrogen;
G ₂ is —OC 1 -C 4 alkyl, CF ₃ , halo, or CN; and G ₃ is optionally substituted with up to 3 substituents selected from isopropyl or C ₃ -C 10 cycloaliphatic rings Wherein G ₃ is optionally substituted with up to three substituents selected from R ′.

Exemplary G ₃ includes optionally substituted cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl. Or, _{G 3} is an aliphatic chains branched C3 -C8. Exemplary G ₃ includes isopropyl, t-butyl, 3,3-diethyl-prop-3-yl, or 3,3-diethyl-2,2-dimethyl-prop-3-yl.

In another embodiment:
G ₁ is hydrogen;
G ₂ is t-butyl; and G ₃ is t-butyl.

  In another embodiment, the present invention provides compounds of formula A-II:

Provide a compound of or a salt thereof, where:
G ₄ is hydrogen, halo, CN, CF ₃ , CHF ₂ , CH ₂ F, optionally substituted C1-C6 aliphatic, aralkyl, or optionally substituted with up to 4 WR ^W substituents A substituted phenyl ring;
G ₅ is hydrogen or C1~C6 aliphatic optionally substituted;
Provided that both G ₄ and G ₅ are not simultaneously hydrogen;
Here, the indole ring system is further optionally substituted with up to three substituents selected from WR ^W.

In one embodiment, G ₄ is hydrogen. Or, G ₅ is hydrogen.

In another embodiment, G ₄ is hydrogen and G ₅ is C 1 -C 6 aliphatic, wherein the aliphatic is optionally C 1 -C 6 alkyl, halo, cyano, or CF _3. depending being substituted, and wherein up to two methylene units of the C1~C6 aliphatic or C1~C6 alkyl is optionally, -CO -, - CONR '- , - CO 2 -, _{-OCO -, - NR'CO 2 -,} - O -, - NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, - SO 2 NR' -, NR Replaced with 'SO _2- , or -NR'SO ₂ NR'-. In another embodiment, R ′ is C1-C4 alkyl.

In another embodiment, G ₄ is hydrogen and G ₅ is cyano, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl, CH ₂ C (O). _OMe, a _{(CH 2) 2 -NHC (O} ) O-tert-But , or cyclopentyl.

In another embodiment, G ₅ is hydrogen and G ₄ is halo, C 1 -C 6 aliphatic or phenyl, and the aliphatic or phenyl is C 1 -C 6 alkyl, halo, cyano, or CF ₃ in optionally substituted up to two methylene units of the C1~C6 aliphatic or C1~C6 _{alkyl, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO _{2 -, - O -, -} NR'CONR '-, - OCONR' -, - NR'CO -, - S -, - NR '-, - SO 2 NR' -, NR'SO 2 -, or -NR Replaced with 'SO ₂ NR'- as necessary. In another embodiment, R ′ is C1-C4 alkyl.

In another embodiment, G ₅ is hydrogen and G ₄ is halo, ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C (O) NH (CH ₂ ) _2. -NMe _2, 2-methoxy-4-chloro - phenyl, pyridin-3-yl, 4-isopropylphenyl, 2,6-dimethoxyphenyl, sec- butylaminocarbonyl, ethyl, t- butyl or piperidin-1-yl, Carbonyl.

In related embodiments of formula A-II, the nitrogen ring atom of the indole ring is substituted with C1-C6 aliphatic, C (O) (C1-C6 aliphatic) or benzyl, wherein the aliphatic or benzyl, C1 -C6 alkyl, halo, optionally substituted with cyano or CF _3-,, where up to two methylene units of said C1 -C6 aliphatic or C1 -C6 alkyl, optionally _{Te, -CO -, - CONR '-} , - CO 2 -, - OCO -, - NR'CO 2 -, - O -, - NR'CONR' -, - OCONR '-, - NR'CO -, - S -, - NR '-, - SO 2 NR' -, NR 'SO 2 -, or is replaced with -NR'SO ₂ NR'-. In another embodiment, R ′ is C1-C4 alkyl.

In another embodiment, the nitrogen ring atom of the indole ring is substituted with acyl, benzyl, C (O) CH ₂ N (Me) C (O) CH ₂ NHMe, or ethoxycarbonyl.

(4. General synthesis scheme)
The compounds of the present invention are readily prepared by methods known in the art. Exemplary methods for the preparation of the compounds of the present invention are described below.

  The following scheme illustrates the synthesis of acid precursors of the compounds of the present invention.

  Synthesis of acid precursors P-IV-A, P-IV-B or P-IV-C:

Synthesis of acid precursors P-IV-A, P-IV-B or P-IV-C:

Synthesis of acid precursors P-IV-A, P-IV-B or P-IV-C

Synthesis of amine precursor P-III-A:

Synthesis of amine precursor P-IV-A:

Synthesis of amine precursor PVAI:

Synthesis of amine precursor PVAI:

Synthesis of amine precursor PVAI:

Synthesis of amine precursor PVAI:

Synthesis of amine precursor PVA-I or PVA-2:

Synthesis of amine precursor PVA-I or PVA-2:

Synthesis of amine precursor PVAI:

Synthesis of amine precursor PVA-3:

Synthesis of amine precursor PVBI:

Synthesis of amine precursor PVBI:

Synthesis of amine precursor PVBI:

Synthesis of amine precursor PVVB-2:

Synthesis of amine precursor PVVB-3:

a) nitration; b) protection; c) [H]
PG = protecting group.
Synthesis of amine precursor PVB-5:

a) When X = Cl, Br, I: R ^X , K ₂ CO ₃ , DMF or CH ₃ CN; When X = OH: R ^X , TFFH, DIEA, THF b) H ₂ , Pd—C EtOH or SnCl ₂ · 2H ₂ O, EtOH or SnCl ₂ · 2H ₂ O, DIEA, EtOH.

  Synthesis of amine precursor PVB-5:

Synthesis of amine precursor VB-5:

Synthesis of amine precursor PVB-5:

Synthesis of amine precursor PVB-5:

Synthesis of amine precursor PVB-5:

Synthesis of amine precursor PVB-5:

Synthesis of amine precursor PVB-5:

Synthesis of amine precursors PVA-3 and PVA-6:

Synthesis of amine precursor PVA-4:

Synthesis of amine precursor PVA-4:

Synthesis of amine precursor P-V-B-4:

Synthesis of amine precursor P-V-B-4:

Synthesis of compounds of formula I:

a) Ar ₁ R ⁷ NH, coupling agent, base, solvent. Examples of conditions used: HATU, DIEA; BOP, DIEA, DMF; HBTU, Et ₃ N, CH ₂ Cl ₂ ; PFPTFA, pyridine.

  Synthesis of compounds of formula I ':

Synthesis of compounds of formula VB-5:

Synthesis of compounds of formula VB-5:

Synthesis of compounds of formula VA-2 and VA-5:

Synthesis of compounds of formula VB-2:

a) When PG = BOC: TFA, CH ₂ Cl ₂ ; When PG = Ac: NaOH or HCl, EtOH or THF.

  Synthesis of compounds of formula VA-2:

a) When PG = BOC: TFA, CH ₂ Cl ₂ .

a) When PG = BOC: TFA, CH ₂ Cl ₂ ; b) ROCOCl, Et ₃ N, DMF.

  (Synthesis of Compound of Formula VA-4)

a) When PG = BOC: TFA, CH ₂ Cl ₂ ; b) When R ^W = CO ₂ R; ROCOCl, DIEA, MeOH.

In the above scheme, the radical R used is a substituent. For example, R ^W are as defined hereinabove. Those skilled in the art will readily appreciate that suitable synthetic routes for the various substituents of the present invention are synthetic routes in which the reaction conditions and processes used do not modify the intended substituents.

(5. Use, formulation and administration)
(Pharmaceutically acceptable composition)
As discussed above, the present invention provides compounds that are useful as modulators of ABC transporters and are therefore useful for treating the following diseases, disorders or conditions: cystic fibrosis Hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency (eg, protein C deficiency), type I hereditary angioedema, lipid processing deficiency (eg, familial hypercholesterolemia), type I chyle , Beta-lipoproteinemia, lysosomal storage diseases (eg, I-cell disease / pseudo-Harler syndrome, mucopolysaccharidosis), Sandhoff disease / Tay-Sachs disease, type II Crigler-Najjar syndrome, multiglandular endocrine Disability / Hyperinsemia, diabetes mellitus, laron dwarfism, myeloperoxidase se) deficiency, primary hypoparathyroidism, melanoma, type I glycanosis CDG, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI) Neurophysical DI, Neurogenic DI, Charcot-Marie-Tooth disease, Perizaeus-Merzbacher disease, neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease, amyotrophic lateral cord) Sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neuropathies (eg Huntington's disease, type I spinocerebellar ataxia, spinal and medullary muscular atrophy, dentate nucleus red nucleus pallidal Louis) Somatic degeneration and myotonic dystrophy) Not only spongiform encephalopathy (eg, hereditary Creutzfeldt-Jakob disease (due to a deficiency in prion protein processing)), Fabry disease and Stausler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD) , Dry eye syndrome or Sjogren's syndrome.

  Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, these compositions comprising any of the compounds as described herein, and optionally A pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

  It will be understood that certain compounds of the present invention may exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or prodrug thereof. In accordance with the present invention, pharmaceutically acceptable derivatives or prodrugs include pharmaceutically acceptable salts, esters, salts of such esters, or directly or indirectly upon administration to a patient in need thereof. In particular, it includes, but is not limited to, any other adduct or derivative that can provide a compound as described elsewhere herein, or a metabolite or residue thereof.

  As used herein, the term “pharmaceutically acceptable salt” refers to humans and lowers within the scope of reliable medical judgment, without undue toxicity, irritation, allergic response, etc. Salt that is suitable for use in contact with animal tissue and is balanced with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salt” is any non-toxic salt or ester salt of a compound of the invention which, upon administration to a recipient, is a compound of the invention or an inhibitory active thereof. A salt that can provide a metabolite or residue either directly or indirectly.

Pharmaceutically acceptable salts are well known in the art. For example, S.M. M.M. Berge et al. Describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic acids and salts derived from organic acids, and salts derived from inorganic bases and salts derived from organic bases. It is done. Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids (eg, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid), or organic acids (eg, acetic acid, oxalic acid) , Maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or formed by using other methods used in the art (eg, ion exchange) A salt of an amino group. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate , Camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptate, glycerophosphate, gluconate, hemisulfate, Heptanoate, hexanoate, hydrogen iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfone Acid salt, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate te), pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, Examples thereof include p-toluenesulfonate, undecanoate, and valerate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-soluble or oil-soluble products or water-dispersible products or oil-dispersible products can be obtained by such quaternization. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, where appropriate. , Lower alkyl sulfonates, and aryl sulfonates).

  As noted above, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which carrier, adjuvant, or vehicle is used herein. Any and all solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners as appropriate to the particular dosage form desired Or it contains emulsifiers, preservatives, solid binders, lubricants and the like. Remington's Pharmaceutical Sciences, 16th edition, E.I. W. Martin (Mack Publishing Co., Easton, Pa, 1980) discloses various carriers used to formulate pharmaceutically acceptable compositions and known techniques for their preparation. Any conventional carrier medium is incompatible with the compounds of the present invention (e.g., by producing any undesirable biological effect, or otherwise, of the pharmaceutically acceptable composition). Except in the case of (by interacting in a deleterious manner with any other component) its use is considered to be within the scope of the present invention. Some examples of substances that can act as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer substances (eg, phosphate) Glycine, sorbic acid or potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt, or electrolyte (eg protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal Silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, wool fat, sugars (eg, lactose, glucose, and sucrose); starches (eg, corn starch, and potatoes) De Cellulose) and derivatives thereof (eg, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate); powdered tragacanth; malt; gelatin; talc; excipients (eg, cocoa butter and suppository wax); oils (eg, Peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil; soybean oil; glycol; (eg, propylene glycol; polyethylene glycol); ester (eg, ethyl oleate and ethyl laurate); agar; , Magnesium hydroxide, aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer, and other non-toxic compatible lubricants Agents (eg, sodium lauryl sulfate) And colorants, mold release agents, coating agents, sweeteners, flavoring agents, and fragrances, preservatives, and antioxidants are also prescribed by the formulator. May be present in the composition according to

(Use of compounds and pharmaceutically acceptable compositions)
In yet another aspect, the present invention provides a method of treating a condition, disease or disorder involving ABC transporter (eg, CFTR) activity. In certain embodiments, the present invention provides a method of treating a condition, disease or disorder associated with ABC transporter deficiency, wherein the method comprises a subject (preferably a mammal). ) Comprising administering a composition comprising a compound of formula (I).

  In certain embodiments, the present invention provides methods of treating the following: cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, clot-fibrinolysis deficiency (eg, protein C deficiency), type I Hereditary angioedema, lipid processing deficiency (eg familial hypercholesterolemia), type I chyleemia, abetalipoproteinemia, lysosomal storage diseases (eg I-cell disease / pseudo-Harler syndrome, mucos Polysaccharidosis), Sandhoff's disease / Tay-Sachs disease, type II Crigler-Najjar syndrome, polygonal endocrine disorder / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, Melanoma, type I glycanosis CDG, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neuro Ishir DI, Neurogenic DI, Charcot-Marie-Tooth disease, Parizaeus-Merzbacher disease, neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease), Spongy as well as various polyglutamine neuropathies (eg, Huntington's disease, spinocerebellar ataxia, spinal and medullary muscle atrophy, erythrocytic red nucleus pallidal degeneration and myotonic dystrophy) Encephalopathy (eg, hereditary Creutzfeldt-Jakob disease (due to a deficiency in prion protein processing)), Fabry disease, Stausler-Schönker syndrome, chronic obstructive pulmonary disease (COPD), dry eye syndrome or Sjogren's syndrome. The method includes the step of administering to the mammal an effective amount of a compound of formula (I) or a composition containing those preferred embodiments shown above.

  According to another preferred embodiment, the present invention provides a method of treating cystic fibrosis, said method comprising, to said mammal, a compound of formula (I) or those preferred embodiments shown above. Administering an effective amount of a composition comprising:

  According to the present invention, an “effective amount” of the compound or pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more of the following: Cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, clot-fibrinolysis deficiency (eg, protein C deficiency), type I hereditary angioedema, lipid processing deficiency (eg, familial hypercholesterolemia) , Type I chyleemia, abetalipoproteinemia, lysosomal storage diseases (eg, I-cell disease / pseudo-Harler syndrome, mucopolysaccharidosis), Sandhoff disease / Tay-Sachs disease, type II Krigler-Nager syndrome, Multiglandular endocrine disorder / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type I glycanosis CDG, congenital hyperthyroidism Disease, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurofischer DI, neurogenic DI, Charcot-Marie-Tooth disease, Parrizaeus-Merzbacher disease, neurodegenerative diseases (eg , Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, various polyglutamine neuropathies (eg, Huntington's disease, type I spinocerebellar ataxia, spinal cord and medulla Spongiform encephalopathy (eg, hereditary Creutzfeldt-Jakob disease (due to a deficiency in prion protein processing)), Fabry disease, as well as muscle atrophy, dentate nucleus, red nucleus, Ryukyu degeneration and myotonic dystrophy , Stausler-Schönker syndrome, chronic obstructive pulmonary disease (COPD), dry eye syndrome or Sjögure Syndrome.

  Compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of the following: cystic Fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency (eg, protein C deficiency), type I hereditary angioedema, lipid processing deficiency (eg, familial hypercholesterolemia), I Type of chyleemia, abetalipoproteinemia, lysosomal storage diseases (eg, I-cell disease / pseudo-Harler syndrome, mucopolysaccharidosis), Sandhoff disease / Taye-Sachs disease, type II Krigler-Najjar syndrome, multigland Endocrine disorders / hyperinsulinemia, diabetes mellitus, laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type I glycanosis CDG, congenital thyroid Hyperfunction, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI), neurofisher DI, neurogenic DI, Charcot-Marie-Tooth disease, Parrizaeus-Merzbacher disease, neurodegenerative disease (Eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease), various polyglutamine neuropathies (eg, Huntington's disease, type I spinocerebellar ataxia, spinal cord and Spongiform encephalopathy (eg, hereditary Creutzfeldt-Jakob disease (due to deficiency in prion protein processing)), Fabry, as well as medullary muscle atrophy, dentate nucleus red nucleus pallidal degeneration and myotonic dystrophy Disease, Stausler-Schönker syndrome, chronic obstructive pulmonary disease (COPD), dry eye syndrome or -Glenn syndrome.

  In one embodiment, the compounds and compositions of the invention are useful for treating or reducing the severity of cystic fibrosis in a patient.

In certain embodiments, the compounds and compositions of the invention are useful for treating or reducing the severity of cystic fibrosis in a patient, wherein the patient is an epithelial and non-respiratory epithelium. The remaining CFTR activity is shown in the apical membrane. The presence of residual CFTR activity on the epithelial surface can be readily detected using methods known in the art (eg, standard electrophysiological, biochemical or histochemical techniques). Such methods use in vitro or in vitro electrophysiological techniques, measurement of sweat or saliva Cl ⁻ concentration, or in vitro biochemical or histochemical techniques for monitoring cell surface density, using CFTR. Identify activity. Using such a method, residual CFTR activity is homozygous or heterozygous for a variety of different mutations (patients homozygous or heterozygous for the most common mutation, ΔF508AESOS). Can be easily detected.

  In another embodiment, the compounds and compositions of the invention are useful for treating or reducing the severity of cystic fibrosis in a patient, wherein the patient is a pharmacological method or gene therapy With residual CFTR activity induced or enhanced. Such a method increases the amount of CFTR present on the cell surface, thereby inducing CFTR activity that was not previously present in the patient or enhancing the level of residual CFTR activity present in the patient. .

  In one embodiment, the compounds and compositions of the invention are useful for treating or reducing the severity of cystic fibrosis in a patient, wherein the patient exhibits a specific CFTR activity Genotypes (eg, class III mutations (regulatory or gating disorders), class IV mutations (conductance changes) or class V mutations (decreased synthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type) I, II, III, IV and V cystic fibrosis Tandem Membrane Conductor Regulator Defects and Opportunities of Therapeutics; Current Opinion in Pulmonary Medicin 6: 521～529,2000)) with a. Other patient genotypes that exhibit residual CFTR activity include patients who are homozygous for one of these classes or any other class of mutations (class I mutations, class II mutations or unclassified mutations). And patients who are heterozygous.

  In one embodiment, the compounds and compositions of the invention are useful for treating or reducing the severity of cystic fibrosis in a patient, wherein the patient has a particular clinical phenotype (Eg, moderate to mild clinical phenotype, typically associated with the amount of residual CFTR activity in the epithelial apical membrane). Such phenotypes include patients with pancreatic sufficiency or patients diagnosed with idiopathic pancreatitis and congenital bilateral deficiency of the vas deferens or mild lung disease.

  The exact amount required will vary from subject to subject, depending on the species, age and general health of the subject, the severity of the infection, the particular drug, its mode of administration and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression “unit dosage form” refers to a physically discrete unit of drug appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The particular effective dose level for any particular patient or organism depends on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; Specific composition of the patient; age, weight, general health, sex and diet of the patient; administration time, route and excretion rate of the specific compound used; duration of treatment; combined with the specific compound used or Drugs used simultaneously; and similar factors well known in the medical field. As used herein, the term “patient” refers to an animal, preferably a mammal, and most preferably a human.

  The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals depending on the severity of the infection being treated, oral, rectal, parenteral, intracisternal, intravaginal, peritoneal cavity. It can be administered internally, topically (by powder, ointment or drop), sublingually, orally or as a nasal spray. In certain embodiments, the compound of the present invention is about 0.01 mg to about 50 mg, about 1 mg per kg body weight of the subject once a day or more per day to achieve the desired therapeutic effect. ~ 25 mg may be administered orally or parenterally.

  Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to these active compounds, these liquid dosage forms contain inert diluents (eg, water and other solvents), solubilizers and emulsifiers (eg, ethyl alcohol, isopropylene) commonly used in the art. Alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil) ), Fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. In addition to inert diluents, these oral compositions can also contain adjuvants such as wetting, emulsifying and suspending agents, sweetening, flavoring and flavoring agents.

  Injectable preparations (eg, sterile injectable aqueous or oleaginous suspension) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. This sterile injectable preparation is also a sterile injectable solution, suspension or emulsion (eg, 1,3-butanediol solution) in a nontoxic parenterally acceptable diluent or solvent. obtain. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.A. S. P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

  These injectable formulations are made, for example, by filtration through a bacteria retaining filter or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. Can be sterilized.

  In order to extend the effectiveness of the compounds of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. Thus, the absorption rate of the compound depends on its dissolution rate, which can depend on the crystal size and crystal shape. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound with biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include (poly (orthoesters)) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

  Compositions for rectal or vaginal administration preferably include suppositories, which contain a non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppositories. Can be prepared by mixing with waxes, which are solid at ambient temperature but liquid at body temperature, and thus dissolve in the rectum or vaginal cavity to release the active compound.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such dosage forms, the active compound comprises at least one inert, pharmaceutically acceptable excipient or carrier (eg, sodium citrate or dicalcium phosphate) and / or a) a filler or Bulking agents (eg starch, lactose, sucrose, glucose, mannitol and silicic acid), b) binders (eg carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia), c) wetting agents (eg glycerol ), D) disintegrants (eg, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate), e) dissolution retardants (eg, barrafin), f) absorption enhancers (Eg, quaternary ammonium compounds), g) humidification (Eg, cetyl alcohol and glycerol monostearate), h) absorbents (eg, kaolin and bentonite clays), and i) lubricants (eg, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) , And mixtures thereof). In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents.

  Similar types of solid compositions can also be used as fillers for soft and hard gelatin capsules using excipients such as high molecular weight polyethylene glycols as well as lactose or lactose. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may contain opacifiers as needed, compositions that release only the active ingredient or preferentially release the active ingredient in a part of the intestine, optionally in a delayed manner. It can be. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers for soft and hard gelatin capsules using excipients such as high molecular weight polyethylene glycols as well as lactose or lactose.

  These active compounds can also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain additional materials other than inert diluents (eg, tableting lubricants and other tableting aids (eg, magnesium stearate and microcrystalline cellulose)) as usual practice. May be contained. In the case of capsules, tablets and pills, these dosage forms may also contain buffering agents. They may contain opacifiers, if necessary, in a part of the intestine where necessary, in a delayed manner, in a delayed manner, only the active ingredient or in a composition that preferentially releases the active ingredient. possible. Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added benefit of controlled delivery of certain compounds into the body. Such dosage forms are prepared by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

  In general, as noted above, the compounds of the present invention are useful as modulators of ABC transporters. Thus, while not wishing to be bound by any particular theory, the compounds and compositions may be of a disease, condition or condition in which ABC transporter hyperactivity or inactivity is associated with a particular disease, condition or disorder. It is particularly useful for treating or reducing the severity of the disorder. Where ABC transporter hyperactivity or inactivity is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as an “ABC transporter-mediated disease, condition or disorder”. Accordingly, in another aspect, the present invention provides a method for treating or reducing the severity of a disease, condition or disorder in which ABC transporter hyperactivity or inactivity is associated with the disease state.

  The activity of the compounds utilized in the present invention as modulators of ABC transporters can be assayed according to the methods generally described in the art and examples herein.

  The compounds of the invention and pharmaceutically acceptable compositions can be used in combination therapy, i.e., the compound and pharmaceutically acceptable composition can be one or more other desired therapeutic methods or medical. It will be understood that it may be administered concurrently with the procedure or before or after. The particular combination of therapies (treatment methods or procedures) for use in the combination regimen takes into account the suitability of the desired treatment and / or procedure and the desired therapeutic effect to be achieved. The therapy used can achieve the desired effect for the same disorder (e.g., the compound of the invention can be administered concurrently with another agent used to treat the same disorder), or It is also understood that they can achieve different effects (eg, control of any side effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as “appropriate for the disease or condition to be treated” .

  In one embodiment, the additional agent is selected from mucolytic agents, bronchodilators, antibiotics, anti-infective agents, anti-inflammatory agents, CFTR modulators other than the compounds of the present invention, nutrients.

  The amount of additional therapeutic agent present in the composition of the present invention is below the amount normally administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition containing that therapeutic agent as the only therapeutically active agent.

  The compounds of the invention or their pharmaceutically acceptable compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, prosthetic valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, generally comprises a composition for coating an implantable device comprising a compound of the present invention as described above, and in the classes and subclasses herein, of the implantable device. A carrier suitable for coating is included. In yet another aspect, the present invention is generally coated with a carrier suitable for coating the implantable device, in compositions and classes herein, including the compounds of the invention as described above, and classes and subclasses herein. Including implantable devices. General preparations of suitable coatings and coated implantable devices are described in US Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coating is typically a biocompatible polymeric material (eg, hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof). This coating can optionally be further coated with a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof, which topcoats provide controlled release characteristics in the composition. Can be provided.

  Another aspect of the present invention relates to modulating the activity of ABC transporters in a biological sample or patient (eg, in vitro or in vivo), the method comprising administering to the patient a compound of formula I or a composition comprising the compound Or contacting the biological sample with a compound of formula I or a composition comprising the compound. As used herein, the term “biological sample” refers to a cell culture or extract thereof; a biopsy material obtained from a mammal or extract thereof; and blood, saliva, urine, stool, Examples include, but are not limited to, semen, tears or other body fluids or extracts thereof.

  In biological samples, modulation of ABC transporter (eg, CFTR) activity is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of ABC transporters in biological and pathological phenomena; and the comparative evaluation of novel modulators of ABC transporters.

  In yet another embodiment, a method is provided for modulating the activity of an anion channel in vitro or in vivo, comprising contacting the channel with a compound of formula (I). In a preferred embodiment, the anion channel is a chloride ion channel or a bicarbonate ion channel. In other preferred embodiments, the anion channel is a chloride ion channel.

  In an alternative embodiment, the present invention provides a method of increasing the number of functional ABC transporters in a cell membrane, the method comprising contacting the cell with a compound of formula (I). As used herein, the term “functional ABC transporter” means an ABC transporter capable of transport activity (transport activity). In a preferred embodiment, this functional ABC transporter is CFTR.

  According to another preferred embodiment, the activity of the ABC transporter is measured by measuring the membrane potential potential. Means for measuring the potential difference across the membrane of this biological sample (biological sample) include methods known in the art (eg, optical membrane potential assays or other electrophysiological methods). Any of them may be used.

  The optical membrane potential assay described above is described in Gonzalez and Tsien (Gonzalez, JE and RY Tsien (1995) “Voltage sensing by fluorescence transfer insencele cells 80” Bio694. , And Gonzalez, JE and RY Tsien (1997) "Improved indicators of cell membrane potential that fluoresceence resenceence energy transfer 9) RE4, Chem. The Voltage / Ion Probe Reader (VIPR) (Gonzalez, JE, K. Odes, et al. (1999) “Cell-based assignments and instrumentation for screening for channels 1—DrugT4” Drug4: 439) and used with instruments for measuring fluorescence changes.

A voltage-sensitive assay as described above consists of DiSBAC ₂ (3), a membrane-soluble voltage-sensitive dye, and CC2-DMPE, a fluorescent phospholipid that binds to the outer surface leaflet of the cell membrane and acts as a donor for FRET. Based on changes in fluorescence resonance energy transfer (FRET) between. A change in membrane potential (V _m ) redistributes negatively charged DiSBAC ₂ (3) across the cell membrane and changes the amount of energy transfer from CC2-DMPE accordingly. Changes in fluorescence can be monitored using VIPR ^™ II, an integrated liquid handler / fluorescence detector designed to perform cell-based screening in 96-well or 384-well microtiter plates. .

  In another aspect, the present invention provides a kit for use in measuring the activity of an ABC transporter or fragment thereof in a biological sample in vitro or in vivo, the kit comprising (i) formula ( A composition comprising a compound of I) or an embodiment as described above; and (ii) an instruction, which comprises: a) contacting the biological sample with the composition as described above; and b) ABC trans Instruction for measuring porter or fragment activity. In one embodiment, the kit comprises a) contacting the biological sample with yet another composition, b) measuring the activity of the ABC transporter or fragment thereof in the presence of the added compound, And c) further comprising instructions for comparing the activity of the ABC transporter in the presence of the other compound with the density of the ABC transporter in the presence of the composition of formula (I). In a preferred embodiment, the kit is used to measure the density of CFTR.

  In order to more fully understand the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

Example 1
(General scheme for preparing the acid moiety)

(Specific example: 2-phenylaminomethylene-malonic acid diethyl ester)

A mixture of aniline (25.6 g, 0.28 mol) and diethyl 2- (ethoxymethylene) malonate (62.4 g, 0.29 mol) was heated at 140-150 ° C. for 2 hours. The mixture was cooled to room temperature and dried under reduced pressure to give 2phenylaminomethylene-malonic acid diethyl ester as a solid, which was used in the next step without further purification.

(4-hydroxyquinoline-3-carboxylic acid ethyl ester)
In a 1 L three-necked flask equipped with a mechanical stirrer was charged 2-phenylaminoethylene-aronic acid diethyl ester (26.3 g, 0.1 mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). The mixture was heated to about 70 ° C. and stirred for 4 hours. The mixture was cooled to room temperature and filtered. The residue was treated with aqueous Na ₂ CO ₃ solution, filtered, washed with water and dried. 4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a light brown solid (15.2 g, 70%). This crude product was used in the next step without further purification.

(A-1; 4-oxo-1,4-dihydroquinoline-3-carboxylic acid)
4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred at reflux for 2 hours. After cooling, the mixture was filtered and the filtrate was acidified to pH 4 using 2N NCl. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale solid. (10.5 g, 92%).

(Specific example: A-2; 6-fluoro-4-hydroxy-quinoline-3-carboxylic acid)

6-Fluoro-4-hydroxy-quinoline-3-carboxylic acid (A-2) was synthesized according to the above general scheme starting with 4-fluoro-phenylamine. Overall yield (53%).

(Example 2)

(2-Bromo-5-methoxy-phenylamine)
A mixture of 1-bromo-4-methoxy-2-nitrobenzene (10 g, 43 mmol) and Raney Ne (5 g) in ethanol (100 mL) was stirred under H ₂ (1 atm) for 4 hours at room temperature. Raney Ni was filtered off and the filtrate was concentrated under reduced pressure. The resulting solid was purified by column chromatography to give 2-bromo-5-methoxyphenylamine (7.5 g, 86%).

(2-[(2-Bromo-5-methoxy-phenylamino) -methylene] -malonic acid diethyl ester)
A mixture of 2-bromo-5-methoxyphenylamine (540 mg, 2.64 mmol) and diethyl 2- (ethoxymethylene) malonate (600 mg, 2.7 mmol) was stirred at 100 ° C. for 2 hours. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy-phenylamino) -methylene] -malonic acid diethyl ester as a yellow solid (0 .8 g, 81%).

(8-Bromo-5-methoxy-4-oxo-1,4dihydro-quinoline-3-carboxylic acid ethyl ester)
2-[(2-Bromo-5-methoxy-phenylamino) -methylene] -malonic acid diethyl ester (9 g, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at 120 ° C. The mixture was stirred at this temperature for an additional 30 minutes and then cooled to room temperature. Absolute ethanol (30 mL) was added and the resulting mixture was refluxed for 30 minutes. The mixture was basified with aqueous sodium bicarbonate at 25 ° C. and extracted with EtOAc (4 × 100 mL). The organic layers were combined, dried and the solvent was evaporated to give 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2.3 g, 30%).

(5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester)
8-Bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3carboxylic acid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol), 10% Pd A mixture of / C (100 mg) in glacial acetic acid (50 ml) was stirred under H ₂ (2.5 atm) overnight. The catalyst was removed by filtration and the reaction mixture was concentrated under reduced pressure. The resulting oil was dissolved in CH ₂ Cl ₂ (100 mL) and washed with aqueous sodium bicarbonate and water. The organic layer was dried, filtered and concentrated. The crude product was purified by column chromatography to give 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester as a yellow solid (1 g, 57%).

(A-4; 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid)
A mixture of 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (1 gg, 7.1 mmol) in 10% NaOH solution (50 mL) was heated to reflux overnight, then Cooled to room temperature. This mixture was extracted with ether. The aqueous layer was separated and acidified with concentrated HCl solution to pH 1-2. The resulting precipitate was collected by filtration to give 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-4) (530 mg, 52%).

Example 3

(Sodium 2- (mercapto-phenylamino-methylene) -malonic acid diethyl ester)
To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mmol) in Et ₂ O, ethyl malonate (24 g, 0.15 mol) was added dropwise at room temperature over 30 minutes. Then phenyl isothiocyanate (20.3 g, 0.15 mol) was added dropwise at room temperature overnight with stirring. The solid was filtered, washed with anhydrous ether (200 mL) and dried under reduced pressure to give sodium 2- (mercapto-phenylamino-methylene) -malonic acid diethyl ester as a pale yellow powder ( 46 g, 97%).

(2- (Methylsulfanyl-phenylamino-methylene) -malonic acid diethyl ester)
Over a period of 30 minutes, methyl iodide (17.7 g, 125 mmol) was added to DMF (33 g, 104 mmol) of sodium 2- (mercapto-phenylamino-methylene) -malonic acid diethyl ester (33 g, 104 mmol) cooled in an ice bath. 100 mL) was added dropwise to the solution. The mixture was stirred at room temperature for 1 hour and then poured into ice water (300 mL). The resulting solid was collected by filtration, washed with water and dried to give 2- (methylsulfanyl-phenylamino-methylene) -malonic acid diethyl ester as a pale yellow solid (27 g, 84%). .

(4-hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester)
A mixture of 2- (methylsulfanyl-phenylamino-methylene) malonic acid diethyl ester (27 g, 87 mmol) in 1,2-dichlorobenzene (100 mL) was heated to reflux for 1.5 hours. The solvent was removed under reduced pressure and the oily residue was triturated with hexanes to give a pale yellow solid, which was purified by preparative HPLC to give 4-hydroxy-2-methylsulfanyl-quinoline. -3-Carboxylic acid ethyl ester (8 g, 35%) was obtained.

(A-16; 2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid)
4-Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g, 30 mmol) was heated to reflux in NaOH solution (10%, 100 mL) for 1.5 hours. After cooling, the mixture was acidified to pH 4 with concentrated HCl. The resulting solid was terminated by filtration and washed with water (100 mL) and MeOH (100 mL) to give 2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-16). , Obtained as a white solid (6 g, 85%).

Example 4

(2,2,2-trifluoro-N-phenyl-acetimidoyl chloride)
A mixture of Ph ₃ P (138.0 g, 526 mmol), Et ₃ N (21.3 g, 211 mmol), CCl ₄ (170 mL) and TFA (10 g, 175 mmol) was stirred in an ice bath for 10 minutes. Aniline (19.6 g, 211 mmol) was dissolved in CCl4 (20 mL) and added. The mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure and hexane was added. The precipitates (Ph ₃ PO and Ph ₃ P) were filtered off and washed with hexane. The filtrate was distilled under reduced pressure to give 2,2,2-trifluoro-N-phenyl-acetimidoyl chloride (19 g), which was used in the next step without further purification.

(2- (2,2,2-trifluoro-1-phenylimino-ethyl) -malonic acid diethyl ester)
To a suspension of NaH (3.47 g, 145 mmol, 60% in mineral oil) in THF (200 mL) was added diethyl malonate (18.5 g, 116 mmol) at 0 ° C. The mixture was stirred at this temperature for 30 minutes and 2,2,2-trifluoro-N-phenyl-acetimidoyl chloride (19 g, 92 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with CH ₂ Cl ₂ and washed with saturated bicarbonate solution and brine. The combined organic layers were dried over Na 2 SO 4, filtered and concentrated to give 2- (2,2,2-trifluoro-1-phenylimino-ethyl) -malonic acid diethyl ester, which was further Used directly in the next step without purification.

(4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester)
2- (2,2,2-trifluoro-1-phenyl meaning -ethyl) -malonic acid ethyl ester was heated at 210 degrees for 1 hour with continued stirring. The mixture was purified by column chromatography (petroleum ether) to give 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (12 g, 24% over 3 steps).

(A-15; 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid)
A suspension of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH was heated to reflux for 2 hours. After cooling, dichloromethane was added and the aqueous phase was separated and acidified to pH 4 with concentrated HCl. The resulting precipitate was collected by filtration and washed with water and Et ₂ O to give 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (A-15) (3.6 g, 80%).

(Example 5)

(3-amino-cyclohex-2-enone)
A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH ₄ (38.5 g, 0.5 mol) in toluene was heated to reflux for 5 hours using a Dean-Stark apparatus. . The resulting oily layer was separated and concentrated under reduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90%), which was used in the next step without further purification. Used directly.

(2-[(3-oxo-cyclohex-1-enylamino) -methylene] -malonic acid diethyl ester)
A mixture of 3-amino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2- (ethoxymethylene) malonate (6.7 g, 31.2 mmol) was stirred at 130 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to give 2-[(3-oxy-cyclohex-1-enylamino) -methylene]- Malonic acid diethyl ester was obtained (7.5 g, 90%).

(4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester)
A mixture of 2-[(3-oxo-cyclohex-1-ethylamino) -methylene] -malonic acid diethyl ester (2.8 g, 1 mmol) and diphenyl ether (20 mL) was refluxed for 15 minutes. After cooling, n-hexane (80 mL) was added. The resulting solid was isolated by filtration and recrystallized from methanol to give 4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester ( 1.7 g, 72%).

(5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester)
To a solution of 4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (1.6 g, 6.8 mmol) in ethanol (100 mL) was added iodine ( 4.8 g, 19 mmol) was added. The mixture was refluxed for 19 hours and then concentrated under reduced pressure. The resulting solid was washed with blooming water, acetone and water, then recrystallized from DMF to give 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 43%).

(A-3; 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid)
A mixture of 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (700 mg, 3 mmol) in 10% NaOH (20 ml) was heated to reflux overnight. After cooling, the mixture was extracted with ether. The aqueous phase was separated and acidified with concentrated HCl to pH 1-2. The resulting precipitate was collected by filtration to give 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-3) (540 mg, 87%).

(Example 6)

(2,4-dichloroquinoline)
A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl ₃ was heated to reflux for 2 hours. After cooling, the solvent was removed under reduced pressure to give 2,4-dichloroquinoline, which was used without further purification.

(2,4-dimethoxyquinoline)
To a suspension of 2,4-dichloroquinoline in MeOH (100 mL) was added sodium methoxide (50 g). The mixture was heated to reflux for 2 days. After cooling, the mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in water and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 2,4-dimethoxyquinoline as a white solid (13 g, 74% over 2 steps).

(Ethyl 2,4-dimethoxyquinoline-3-carboxylate)
To a solution of 2,4-dimethoxyquinoline (11.5 g, 60.8 mmol) in anhydrous THF, n-BuLi (2.5 M in hexane, 48.6 mL, 122 mmol) was added dropwise at 0 ° C. After stirring for 1.5 hours at 0 ° C., the mixture was added to a solution of ethyl chloroformate in anhydrous THF and stirred for an additional 30 minutes at 0 ° C. and then overnight at room temperature. The reaction mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / EtOAc = 50/1) to give ethyl 2,4-dimethoxyquinoline-3-carboxylate (9.6 g, 60%).

(A-17; 2,4-dimethoxyquinoline-3-carboxylic acid)
Ethyl 2,4-dimethoxyquinoline-3-carboxylate (1.5 g, 5.7 mmol) was heated to reflux in NaOH solution (10%, 100 mL) for 1 hour. After cooling, the mixture was acidified to pH 4 with concentrated HCl. The resulting precipitate was collected by filtration and washed with water and ether to give 2,4-dimethoxyquinoline-3-carboxylic acid (A-17) as a white solid (670 mg, 50%).

(Commercial acid)

(Amine part)
(N-1-substituted 6-aminoindole)
Example 1
General scheme:

Concrete example:

(1-Methyl-6-nitro-1H-indole)
6-nitroindole (4.05g, 25mmol), in solution in DMF (50 _mL), was _{K 2 CO 3 (8.63g, 62.5mmol} ) and MeI (5.33g, 37.5mmol) was added. After stirring at room temperature overnight, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the product 1-methyl-6-nitro-1H-indole (4.3 g, 98%).

(B-1; 1-methyl-1H-indol-6-ylamine)
A suspension of 1-methyl-6-nitro-1H-indole (4.3 g, 24.4 mmol) and 10% Pd—C (0.43 g) in EtOH (50 mL) was added under H ₂ (1 atm). At room temperature overnight. After filtration, the filtrate was concentrated and acidified with HCl-MeOH (5 mol / L) to give 1-methyl-1H-indol-6-ylamine hydrochloride (B-1) (1.74 g, 49%). Obtained as a gray powder.

Other examples:

(B-2; 1-benzyl-1H-indol-6-ylamine)
1-Benzyl-1H-indole-6-ylamine (B-2) was synthesized according to the above general scheme starting with 6-nitroindole and benzyl bromide. Overall yield (about 40%). HPLC retention time 2.19 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 223.3m / z ( MH +).

(B-3; 1- (6-Amino-indol-1-yl) ethanone 1- (6-Amino-indol-1-yl) -ethanone (B-3) starting with 6-nitroindole and acetyl chloride The overall yield (about 40%), HPLC retention time 0.54 min, 10-99% CH ₃ CN, 5 min run; ESI-MS 175.1 m / z ( MH ^<+> ).

  (Example 2)

({[2- (tert-Butoxycarbonyl-methyl-amino) -acetyl] -methyl-amino} -acetic acid ethyl ester)
To a stirred solution of (tert-butoxycarbonyl-methyl-amino) -acetic acid (37 g, 0.2 mol) and Et ₃ N (60.6 g, 0.6 mol) in CH ₂ Cl ₂ (300 mL) was added isobutyl chloroformate. (27.3 g, 0.2 mmol) was added dropwise at −20 ° C. under nitrogen. After stirring for 0.5 hour, methyl-mesh -acetic acid ethyl ester hydrochloride (30.5 g, 129 mmol) was added dropwise at -20 ° C. The mixture was warmed to room temperature (about 1 hour) and quenched with water (500 mL). The organic layer was separated, washed with 10% citric acid solution, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether / EtOAc 1: 1) to give {[2- (tert-butoxycarbonyl-methyl-amino) -acetyl] -methyl-amino} -acetic acid ethyl ester. (12.5 g, 22%).

({[2- (tert-Butoxycarbonyl-methyl-amino) -acetyl] -methyl-amino} -acetic acid)
{[2- (tert-Butoxycarbonyl-methyl-amino) -acetyl] -methyl-amino} -acetic acid ethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H ₂ O ( A suspension in 20 mL) and THF (100 mL) was stirred overnight. The volatile solvent was removed under reduced pressure and the residue was extracted with ether (2 × 100 mL). The aqueous phase was acidified with dilute HCl solution to pH 3 and then extracted with CH ₂ Cl ₂ (2 × 300 mL). The combined organic layers are washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give {[2- (tert-butoxycarbonyl-methyl-amino) -acetyl] -methyl-amino} -acetic acid. Was obtained as a colorless oil (10 g, 90%).

(Methyl ({methyl- [2- (6-nitro-indol-1-yl) -2-oxo-ethyl] -carbamoyl} -methyl) -carbamic acid tert-butyl ester)
{[2- (tert-Butoxycarbonyl-methyl-amino) -acetyl] -methyl-amino} acetic acid (13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 mL). To the mixture was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 minutes. A solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60 degrees for 18 hours. The solvent was evaporated and the composition mixture was repartitioned between EtOAc and water. The organic layer was separated, washed with water (3 times), dried over Na ₂ SO ₄ and concentrated, diethyl ether was added followed by EtOAc. The resulting solid was collected by filtration, washed with diethyl ether and dried to give methyl-({methyl- [2- (6-nitro-indol-1-yl) -2-oxo-ethyl] -carbamoyl. } -Methyl) -carbamic acid tert-butyl ester was obtained (6.42 g, 30%).

(B-26; ({[2- (6-Amino-indol-1-yl) -2-oxo-ethyl] -methyl-carbamoyl} -methyl) -carbamic acid tert-butyl ester)
Methyl-({methyl- [2- (6-nitro-indol-1-yl) -2-oxo-ethyl] -carbamoyl} -methyl) -carboxylic acid tert-butyl ester (12.4 g, 30.6 mmol) and , SnCl ₂ .2H ₂ O (34.5 g, 153.2 mmol) and DIEA (74.8 mL, 429 mmol) in ethanol (112 mL) were heated to 70 ° C. for 3 hours. Water and EtOAc were added and the mixture was filtered through a short plug of celite. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated to ({[2- (6-amino-indol-1-yl) -2-oxo-ethyl] -methyl-carbamoyl} -methyl. ) -Methyl-carbamic acid tert-butyl ester (B-26) was obtained (11.4 g, quantitative). HPLC retention time 2.11 minutes, the implementation of _10~90% CH 3 CN, 5 min; ESI-MS 375.3m / z ( MH +).

(2-substituted 6-aminoindole)
Example 1

(B-4-a; (3-nitro-phenyl) -hydrazine hydrochloride)
3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H ₂ O (40 mL) and 37% HCl (40 mL) at 0 ° C., then in 37% HCl (100 mL). SnCl ₂ .H ₂ O (135.5 g, 0.6 mol) was added at that temperature. After stirring at 0 ° C. for 0.5 h, the solid was isolated by filtration and washed with water to give (3-nitro-phenyl) -hydrazine hydrochloride (B-4-a) (27. 6g, 73%).

(2-[(3-Nitro-phenyl) -hydrazono] -propionic acid ethyl ester)
(3-Nitro-phenyl) -hydrazine hydrochloride (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) were added to ethanol (300 mL). 2) Dissolved. The mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 2-[(3-nitro-phenyl) -hydrazono] -propionic acid ethyl ester, which was used directly in the next step.

(B-4-b; 4-nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-1H-indole-2-carboxylic acid ethyl ester)
2-[(3-Nitro-phenyl) -hydrazono] -propionic acid ethyl ester obtained from the previous step was dissolved in toluene (300 mL). PPA (30 g) was added. The mixture was heated at reflux overnight and then cooled to room temperature. The solvent was removed to obtain a mixture (B-4-b) of 4-nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-1H-indole-2-carboxylic acid ethyl ester. (15 g, 40%).

(B-4; 2-methyl-1H-indol-6-ylamine)
To a suspension of LiAlH ₄ (7.8 g, 0.21 mol) in THF (300 mL) was added 4-nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-1H-indole-2-carboxylic acid. A mixture with acid ethyl ester (B-b) (6 g, 25.7 mmol) in THF (50 mL) was added dropwise at 0 ° C. under N ₂ . The mixture was heated at reflux overnight and then cooled to 0 ° C. H ₂ O (7.8 mL) and 10% NaOH (7.8 mL) were added to the mixture at 0 ° C. Insoluble solids were removed by filtration. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. The composition residue was purified by column chromatography to give 2-methyl-1H-indol-6-ylamine (B-4) (0.3 g, 8%).

(Example 2)

(6-Nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid)
A mixture of 4-nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-1H-indole-2-carboxylic acid ethyl ester (B-4-b) (0.5 g, 2.13 mmol) ( 10% NaOH (20 mL)) was heated to reflux overnight and then cooled to room temperature. This mixture was extracted with ether. The aqueous phase was separated and acidified with HCl to pH 1-2. The resulting solid was isolated by filtration to give a mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (0.3 g, 68%) .

(6-Nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid amide)
A mixture of 6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and SOCl ₂ (50 mL, 64 mmol) in benzene (150 mL). Refluxed for 2 hours. Benzene and excess SOCl2 were removed under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ (250 mL). NH ₄ OH (21.76 g, 0.32 mol) was added dropwise at 0 ° C. The mixture was stirred at room temperature for 1 hour. The resulting solid was isolated by filtration to give a composition mixture (9 g, 68%) of 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid amide. This was used directly in the next step.

(6-Nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile)
A mixture of 6-nitro-1H-indole-2-carboxylic acid amide and 4-nitro-1H-indole-2-carboxylic acid amide (5 g, 24 mmol) was dissolved in CH ₂ Cl ₂ (200 mL). Et ₃ N (24.24 g, 0.24 mol) was added followed by (CF ₃ CO) ₂ O (51.24 g, 0.25 mol) at room temperature. The mixture was stirred for 1 hour and poured into water (100 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The composition residue was purified by column chromatography to give a mixture of 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, 55% ).

(B-5; 6-amino-1H-indole-2-carbonitrile)
Between 6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile (2.5 g, 13.4 mmol) and Raney Ni (500 mg) in EtOH (50 mL). The mixture was stirred at room temperature for 1 h under H ₂ (1 atm). Raney Ni was filtered off. The filtrate was evaporated under reduced pressure and purified by column chromatography to give 6-amino-1H-indole-2-carbonitrile (B-5) (1 g, 49%).

Example 3

(2,2-Dimethyl-N-o-tolyl-propionamide)
2,2-Sprinkle into a solution of o-tolylamine (21.4 g, 0.20 mol) and Et ₃ N (22.3 g, 0.22 mol) in CH ₂ Cl ₂ (25.3 g, 0.21 mol) was added at 10 ° C. The mixture was stirred at room temperature overnight, washed with aqueous HCl (5%, 80 mL), saturated NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2,2- Dimethyl-N-o-tolyl-proionamide was obtained (35.0 g, 92%).

(2-tert-butyl-1H-indole)
To a solution of 2,2-dimethyl-N-o-tolyl-propionamide (30.1 g, 159 mmol) in dry THF (100 mL) was added n-BuLi (2.5 M in hexane, 190 mL) at 15 ° C. did. The mixture was stirred at 15 ° C. overnight, cooled in an ice-water bath and treated with saturated NH ₄ Cl solution. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The combined courageous layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-tert-butyl-1H-indole (23.8 g, 88%).

(2-tert-butyl-2,3-dihydro-1H-indole)
To a solution of 2-tert-butyl-1H-indole (5.0 g, 29 mmol) in AcOH (20 mL) was added NaBH ₄ at 10 ° C. The mixture was stirred at 10 ° C. for 20 minutes, treated dropwise with H ₂ O while cooling with ice, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to give a mixture of starting material and 2-tert-butyl-2,3-dihydro-1H-indole (4.9 g). Which was used directly in the next step.

(2-tert-butyl-6-nitro-2,3-dihydro-1H-indole)
To a mixture of 2-tert-butyl-2,3-dihydro-1H-indole and 2-tert-butyl-1H-indole (9.7 g) in H ₂ SO ₄ (98%, 80 mL) was added KNO _3. (5.6 g, 55.7 mmol) was added slowly at 0 ° C. The reaction mixture was stirred at room temperature for 1 h, carefully poured onto crushed ice, basified with Na ₂ CO ₃ to pH ˜8 and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (4.0 g, 32% over 2 steps).

(2-tert-butyl-6-nitro-1H-indole)
To a solution of 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ at room temperature. After refluxing for 2.5 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80%).

(B-6; 2-tert-butyl-1H-indol-6-ylamine)
To a solution of 2-tert-butyl-5-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Ni (0.2 g). The mixture was stirred at room temperature under H ₂ (1 atm) for 3 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-1H-indol-6-ylamine (B-6) (1.0 g, 89%).

(3-substituted 6-aminoindole)
Example 1

(N- (3-nitro-phenyl) -N′-propylidene-hydrazine)
Sodium hydroxide solution (10%, 15 mL) was added to a stirred suspension of (3-nitro-phenyl) -hydrazine hydrochloride (B-4-a) (1.89 g, 10 mmol) in ethanol (20 mL). Slowly added until pH 6 was reached. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 hours at room temperature, the mixture is poured into ice water and the resulting precipitate is isolated by filtration, washed with water and dried in air to give N- (3-nitro-phenyl) -N'-propylidene-hydrazine was obtained and used directly in the next step.

(3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole)
A mixture of N- (3-nitro-phenyl) -N′-propylidene-hydrazine dissolved in 85% H ₃ PO ₄ (20 mL) and toluene (20 mL) was heated from 90 ° C. to 100 ° C. for 2 hours. After cooling, toluene was removed under reduced pressure. The resulting oil was basified with 10% NaOH to pH 8. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were dried, filtered and concentrated under reduced pressure to give a mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (1.5 g, 86% over 2 steps) which was used directly in the next step.

(B-7; 3-methyl-1H-indol-6-ylamine)
Mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (3 g, 17 mol) and 10% Pd-C (0.5 g) in ethanol (30 mL) Was stirred overnight at room temperature under H ₂ (1 atm). Pd-C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 3-methyl-1H-indol-6-ylamine (B-7) (0.6 g, 24%).

(Example 2)

(6-Nitro-1H-indole-3-carbonitrile)
To a solution of 6-nitroindole (4.86 g, 30 mmol) in DMF (24.3 mL) and CH ₃ CN (243 mL) was added a solution of ClSO ₂ NCO (5 mL, 57 mmol) in CH ₃ CN (39 mL). The solution was added dropwise at 0 ° C. After the reaction, the reaction was warmed to room temperature and stirred for 2 hours. The mixture was poured into ice water, postponed with saturated NaHCO3 solution until pH 7-8, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).

(B-8; 6-amino-1H-indole-3-carbonitrile)
A suspension of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 24.6 mmol) and 10% Pd—C (0.46 g) in EtOH (50 mL) was added to H ₂ (1 atm). Stir overnight at room temperature. After filtration, the filtrate was concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc = 3/1) to give 6-nitro-1H-indole-3-carbonitrile (B-8). Obtained as a pink powder (1 g, 99%).

Example 3

(Dimethyl- (6-nitro-1H-indol-3-ylmethyl) -amine)
A solution of dimethylamine (25 g, 0.17 mol) and formaldehyde (14.4 mL, 0.15 mol) in acetic acid (100 mL) was stirred at 0 ° C. for 30 minutes. To this solution was added 6-nitro-1H-indole (20 g, 0.12 mol). After stirring for 3 days at room temperature, the mixture was poured into 15% aqueous NaOH solution (500 mL) at 0 ° C. The precipitate was collected by filtration and washed with water to give dimethyl- (6-nitro-1H-indol-3-ylmethyl) -amine (23 g, 87%).

(B-9-a; (6-nitro-1H-indol-3-yl) acetonitrile)
To a mixture of DMF (35 mL) and MeI (74.6 g, 0.53 mol) in water (35 mL) and THF (400 mL) was added dimethyl- (6-nitro-1H-indol-3-ylmethyl) -amine (23 g 0.105 mol) was added. After the reaction mixture was refluxed for 10 minutes, potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was kept at reflux overnight. The mixture was then cooled to room temperature and filtered. The filtrate was washed with brine (300 mL × 3), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography to give (6-nitro-1H-indol-3-yl) -acetonitrile (B-9-a) (7.5 g, 36%).

(B-9; (6-Amino-1H-indol-3-yl) -acetonitrile)
A mixture of (6-nitro-1H-indol-3-yl) -acetonitrile (B-9-a) (1.8 g, 74.5 mmol) and 10% Pd-C (300 mg) in EtOH (50 mL). Stir at room temperature under H ₂ (1 atm) for 5 hours. Pd—C was removed by filtration and the filtrate was evaporated to give (6-amino-1H-indol-3-yl) -acetonitrile (B-9) (1.1 g, 90%).

Example 4

([2- (6-Nitro-1H-indol-3-yl) ethyl] -carbamic acid tert-butyl ester)
To a solution of (6-nitro-1H-indol-3-yl) acetonitrile (B-9-a) 8.6 g, 42.8 mmol) in dry THF (200 mL), 2M borane-dimethylsulfide complex in THF. A solution of (214 mL, 0.43 mol) was added at 0 ° C. The mixture was heated to reflux overnight under nitrogen. The mixture was then cooled to room temperature and a solution of (Boc) ₂ O (14 g, 64.2 mmol) and Et ₃ N (89.0 mL, 0.64 mol) in THF was added. The reaction mixture was left stirring overnight and then poured into ice water. The organic layer was separated and the aqueous phase was extracted with EtOAc (200 × 3 mL). The combined organic layers were washed with water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to give [2- (6-nitro-1H-indol-3-yl) -ethyl] -carbamic acid tert-butyl ester (5 g, 38%).

(B-10; [2- (6-Amino-1H-indol-3-yl) -ethyl] -carbamic acid tert-butyl ester)
A mixture of [2- (6-nitro-1H-indol-3-yl) -ethyl] -carbamic acid tert-butyl ester (5 g, 16.4 mmol) and Raney Ni (1 g) in EtOH (100 mL). Stir at room temperature under H ₂ (1 atm) for 5 hours. Raney Ni was filtered off and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography to give [2- (6-Amino-1H-indol-3-yl) -ethyl] -carboxylic acid tert-butyl ester (B-10) (3 g, 67 %).

(Example 5)
General scheme:

Concrete example;

(3-tert-butyl-6-nitro-1H-indole)
To a mixture of 6-nitroindole (1 g, 6.2 mmol), zinc trifluoromethanesulfonate (2.06 g, 5.7 mmol) and TBAI (1.7 g, 5.16 mmol) in anhydrous toluene (11 mL) was added DIEA. (1.47 g, 11.4 mmol) was added under nitrogen at room temperature. The reaction mixture was stirred at 120 ° C. for 10 minutes and then t-butyl bromide (0.707 g, 5.16 mmol) was added. The resulting mixture was stirred at 120 ° C. for 45 minutes. The solid is filtered off and the filtrate is concentrated to dryness and purified by column chromatography on silica gel (petroleum ether / EtOAc 20: 1) to give 3-tert-butyl-6-nitro-1H-indole. , Obtained as a yellow solid (0.25 g, 19%).

(B-11; 3-tert-butyl-1H-indol-6-ylamine)
A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 13.7 mmol) and Raney Ni (0.5 g) in ethanol at room temperature under H3 (1 atm) for 3 hours. Stir. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (petroleum ether / EtOAc 4: 1) to give 3-tert-butyl-1H-indol-6-ylamine (B-11) as a gray solid (2 0.0 g, 77.3%).

Other examples:

(B-12; 3-ethyl-1H-indol-6-ylamine)
3-Ethyl-1H-indol-6-ylamine (B-12) was synthesized according to the general scheme above starting with 6-nitroindole and ethyl bromide. Overall yield (42%). HPLC retention time 1.95 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 161.3m / z ( MH +).

(B-13; 3-isopropyl-1H-indol-6-ylamine)
3-Isopropyl-1H-indol-6-ylamine (B-13) was synthesized according to the general scheme above starting with 6-nitroindole and isopropyl iodide. Overall yield (17%). HPLC retention time 2.06 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 175.2m / z ( MH +).

(B-14; 3-sec-butyl-1H-indol-6-ylamine)
3-sec-butyl-1H-indol-6-ylamine (B-14) was synthesized according to the above general scheme starting with 6-nitroindole and 2-bromobutane. Overall yield (20%). HPLC retention time 2.32 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 189.5m / z ( MH +).

(B-15; 3-cyclopentyl-1H-indol-6-ylamine)
3-Cyclopentyl-1H-indol-6-ylamine (B-15) was synthesized according to the above general scheme starting with 6-nitroindole and iodo-cyclopentane. Overall yield (16%). HPLC retention time 2.39 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 201.5m / z ( MH +).

(B-16; 3- (2-Ethoxy-ethyl) -1H-indol-6-ylamine)
3- (2-Ethoxy-ethyl) -1H-indol-6-ylamine (B-16) was synthesized according to the above general scheme starting with 6-nitroindole and 1-bromo-2-ethoxy-ethane. Overall yield (15%). HPLC retention time 1.56 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 205.1m / z ( MH +).

(B-17; (6-Amino-1H-indol-3-yl) -acetic acid ethyl ester)
(6-Amino-1H-indol-3-yl) -acetic acid ethyl ester (B-17) was synthesized according to the above general scheme starting with 6-nitroindole and iodo-acetic acid ethyl ester. Overall yield (24%). HPLC retention time 0.95 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 219.2m / z ( MH +).

  (4-substituted 6-aminoindole)

(2-methyl-3,5-dinitro-benzoic acid)
To a mixture of HNO ₃ (95%, 80 mL) and H ₂ SO ₄ (98%, 80 mL), methylbenzoic acid (50 g, 0.37 mol) was slowly added at 0 degrees. After the reaction, the reaction mixture was stirred for 1.5 hours while maintaining the temperature below 30 ° C., poured into ice water and stirred for 15 minutes. The resulting precipitate was collected by filtration and washed with water to give 2-methyl-3,5-dinitro-benzoic acid (70 g, 84%).

(2-methyl-3,5-dinitro-benzoic acid ethyl ester)
A mixture of 2-methyl-3,5-dinitro-benzoic acid (50 g, 0.22 mol) in SOCl ₂ (80 mL) was heated to reflux for 4 hours and then concentrated to dryness. CH ₂ Cl ₂ (50 mL) and EtOH (80 mL) were added. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with EtOAc (3 × 100 mL). The combined extracts were washed with saturated Na ₂ CO ₃ (80 mL), water (2 × 100 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated to dryness to give 2-methyl-3 , 5-Dinitro-benzoic acid ethyl ester was obtained (50 g, 88%).

(2- (2-Dimethylamino-vinyl) -3,5-dinitro-benzoic acid ethyl ester)
A mixture of 2-methyl-3,5-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethyl-amine (32 g, 0.27 mol) in DMF (200 mL) was added 5 Heated for hours. The mixture was poured into ice water, the precipitate was collected by filtration and washed with water to give 2- (2-dimethylamino-vinyl) -3,5-dinitro-benzoic acid ethyl ester ( 11.3 g, 48%).

(B-18; 6-amino-1H-indole-4-carboxylic acid ethyl ester)
A mixture of 2- (2-dimethylamino-vinyl) -3,5-dinitro-benzoic acid ethyl ester (11.3 g, 0.037 mol) and SnCl ₂ (83 g, 0.37 mol) in ethanol was stirred for 4 hours. Heated to reflux. The mixture was concentrated to dryness and the residue was poured into water and basified to pH 8 with saturated Na ₂ CO ₃ solution. The precipitate was filtered off and the filtrate was extracted with ethyl acetate (3 × 100 mL). The combined extracts were washed with water (2 × 100 mL) and brine (150 mL), dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g, 40%).

(5-substituted 6-aminoindole)
Example 1
General scheme:

Concrete example:

(1-Fluoro-5-methyl-2,4-dinitro-benzene)
To a mixed solution of HNO ₃ (60 mL) and H ₂ SO ₄ (80 mL) cooled in an ice bath, 1-fluoro-3-methyl-benzene (27.5 g, 25 mmol) was added at a temperature of 35 ° C. The temperature was not exceeded. The mixture was stirred at room temperature for 30 minutes and poured into ice water (500 mL). The resulting precipitate (about 7: 3 mixture of the desired product and 1-fluoro-3-methyl-2,4-dinitro-benzene) is collected by filtration and from 50 mL of isopropyl ether. Purification by recrystallization gave 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).

([2- (5-Fluoro-2,4-dinitro-phenyl) -vinyl] -dimethyl-amine)
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), dimethoxymethyl-dimethylamine (11.9 g, 100 mmol) and DMF (50 mL) was heated at 100 ° C. for 4 hours. The solution was cooled and poured into water. The red precipitate was collected by filtration, washed thoroughly with water and dried to give [2- (5-fluoro-2,4-dinitro-phenyl) -vinyl] -dimethyl-amine (8 g 63%).

(B-20; 5-fluoro-1H-indol-6-ylamine)
A suspension of [2- (5-fluoro-2,4-dinitro-phenyl) -vinyl] -dimethyl-amine (8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (80 mL) was added to H Stir at room temperature under ₂ (40 psi) for 1 hour. After filtration, the filtrate was concentrated and the residue was purified by chromatography (petroleum ether / EtOAc = 5/1) to give 5-fluoro-1H-indol-6-ylamine (B-20) as brown Obtained as a solid (1 g, 16%).

Other examples:

(B-21; 5-chloro-1H-indol-6-ylamine)
5-Chloro-1H-indol-6-ylamine (B-21) was synthesized according to the above general scheme starting with 1-chloro-3-methyl-benzene. Overall yield (7%).

(B-22; 5-trifluoromethyl-1H-indol-6-ylamine)
5-Trifluoromethyl-1H-indol-6-ylamine (B-21) was synthesized according to the above general scheme starting with 1-methyl-3-trifluoromethyl-benzene. Overall yield (2%).

(Example 2)

(1-Benzenesulfonyl-2,3-dihydro-1H-indole)
To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24 g, 136 mmol) and 2,3-dihydro-1H-indole (14.7 g, 124 mmol) in CH2Cl2 (200 mL) was added Et ₃ in an ice-water bath. N (19 g, 186 mmol) was added dropwise. After the reaction, the mixture was stirred at room temperature overnight, washed with water, dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure to give 1-benzenesulfonyl-2,3-dihydro-1H-indole. (30.9 g, 96%) was obtained.

(1- (1-Benzenesulfonyl-2,3-dihydro-1H-indol-5-yl) -ethanone)
To a stirred suspension of AlCl ₃ (144 g, 1.08 mol) in CH ₂ Cl ₂ (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes. A solution of 1-benzenesulfonyl-2,3-dihydro-1H-indole (46.9 g, 0.18 mol) in CH ₂ Cl ₂ (1070 mL) was added dropwise. The mixture was stirred for 5 hours and quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 1- (1-benzenesulfonyl-2,3-dihydro-1H-indole- 5-yl) -ethanone was obtained (42.6 g, 79%).

(1-Benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole)
To mechanically stirred TFA (1600 mL) at 0 ° C., sodium borohydride (64 g, 1.69 mol) was added over 1 hour. To this mixture was added dropwise a solution of 1- (1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl) -ethanone (40 g, 0.13 mol) in TFA (700 mL) over 1 hour. did. The mixture was stirred at 25 ° C. overnight, diluted with H ₂ O (1600 ml) and basified with sodium hydroxide pellets at 0 ° C. The organic layer was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (16.5 g, 43%).

(5-ethyl-2,3-dihydro-1H-indole)
A mixture of 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05 mol) in HBr (48%, 162 mL) was heated to reflux for 6 hours. The mixture was basified with saturated NaOH solution to pH 9 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 32%).

(5-ethyl-6-nitro-2,3-dihydro-1H-indole)
To a solution of 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 17 mmol) in H ₂ SO ₄ (98%, 20 mL) was added KNO ₃ (1.7 g, 17 mmol) at 0 ° C. Slowly added. After the addition, the mixture was stirred at 0 ° C. to 10 ° C. for 10 minutes, poured carefully into ice, basified to pH 9 with NaOH solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 58%).

(5-ethyl-6-nitro-1H-indole)
To a solution of 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 9.9 mmol) in CH ₂ Cl ₂ (30 mL) was added MnO ₂ (4 g, 46 mmol). . The mixture was stirred at room temperature for 8 hours. The solid was filtered off and the filtrate was concentrated to dryness to give crude 5-ethyl-6-nitro-1H-indole (1.9 g, quantitative).

(B-23; 5-ethyl-1H-indol-6-ylamine)
A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney Ni (1 g) was stirred at room temperature under H ₂ (1 atm) for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-ethyl-1H-indol-6-ylamine (B-23) (760 mg, 48%).

Example 3

(2-Bromo-4-tert-butyl-phenylamine)
To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL) was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at room temperature. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude product was used directly in the next step without further purification.

(2-Bromo-4-tert-butyl-5-nitro-phenylamine)
2-Bromo-4-tert-butyl-phenylamine (162 g, 0.71 mol) was added dropwise to H.sub.2SO.sub.4 (410 ML) at room temperature to give a clear solution, which was then added at -5.degree. Cooled to ~ -10 ° C. A solution of KNO ₃ (82.5 g, 0.82 mol) in H ₂ SO ₄ (410 mL) was added dropwise while maintaining the temperature between −5 ° C. and −10 ° C. Upon completion, the reaction mixture was poured into ice / water and extracted with EtOAc. The combined organic layers were washed with 5% Na ₂ CO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (EtOAc / petroleum ether 1/10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (152 g, 78 %).

(4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine)
To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100 mmol) in toluene (200 mL) and water (100 mL) was added Et ₃ N (27.9 mL, 200 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (2.11 g, 3 mmol) CuI (950 mg, 0.5 mmol) and trimethylsilylacetylene (21.2 mL, 150 mmol) were added under a nitrogen atmosphere. The reaction mixture was heated at 70 ° C. in a sealed pressure flask for 2.5 hours, cooled to room temperature, and filtered through a short plug of celite. The filter cake was washed with EtOAc. The combined filtrate was washed with 5% NH4 OH solution and water, dried over _Na 2 SO _4, and concentrated. The crude product was purified by column chromatography (0-10% EtOAc / petroleum ether) to give 4-tert-butyl-5-nitro-2-triethylsilanylethynyl-phenylamine as a brown viscous liquid. Obtained (25 g, 81%).

(5-tert-butyl-6-nitro-1H-indole)
To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added CuI (8.2 g, 43 mmol) under a nitrogen atmosphere. did. The mixture was heated in a sealed pressure flask at 135 ° C. overnight, cooled to room temperature, and filtered through a short plug of celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (10-20% EtOAc / hexanes) to give 5-tert-butyl-6-nitro-1H-indole as a yellow solid (12.9 g, 69%). .

(B-24; 5-tert-butyl-1H-indol-6-ylamine)
Raney Ni (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67 mmol) in methanol (100 mL). The mixture was stirred for 3 hours at 30 ° C. under hydrogen (1 atm). The catalyst was filtered off. The filtrate was dried over Na ₂ SO ₄ and concentrated. The crude dark brown viscous oil was purified by column chromatography (10-20% EtOAc / petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine (B-24) as a gray solid (11 g, 87%).

Example 4

(5-methyl-2,4-dinitro-benzoic acid)
To a mixture of HNO ₃ (95%, 80 mL) and H ₂ SO ₄ (98%, 80 mL), 3-methylbenzoic acid (50 g, 0.37 mol) was slowly added at 0 ° C. After the addition, the mixture was stirred for 1.5 hours while maintaining the temperature below 30 degrees. The mixture was poured into ice water and stirred for 15 minutes. The precipitate was collected by filtration and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g 84%). To a solution of this mixture in EtOH (150 mL), SOCl ₂ (53.5 g, 0.15 mol) was added dropwise. The mixture was heated to reflux for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 10% Na ₂ CO ₃ solution (120 mL). The organic layer was found to contain 5-methyl-2,4-dinitro-benzoic acid ethyl ester, while the aqueous layer was found to contain 3-methyl-2,6-dinitro-benzoic acid. . The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness to give 5-methyl-2,4-dinitro-benzoic acid ethyl ester (20 g, 20%). .

(5- (2-Dimethylamino-vinyl) -2,4-dinitro-benzoic acid ethyl ester)
A mixture of 5-methyl-2,4-dinitro-benzoic acid ethyl ester (39 g, 0.15 mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL) was stirred at 100 ° C. for 5 hours. Heated. The mixture was poured into ice water and the precipitate was collected by filtration and washed with water to give 5- (2-dimethylamino-vinyl) -2,4-dinitro-benzoic acid ethyl ester (15 g 28%).

(B-25; 5-amino-1H-indole-5-carboxylic acid ethyl ester)
A mixture of 5- (2-dimethylamino-vinyl) -2,4-dinitro-benzoic acid ethyl ester (15 g, 0.05 mol) and Raney Ni (5 g) in EtOH (500 mL) was added to H ₂ (50 psi). The mixture was stirred at room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 6-amino-1H-indole-5-carboxylic acid ethyl ester (B-25) (3 g, 30%).

(Example 5)

(1- (2,3-dihydro-indol-1-yl) -ethanone)
To a suspension of NaHCO ₃ (504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60 g, 0.5 mol) in CH ₂ Cl ₂ (600 mL) cooled in an ice-water bath. Acetyl chloride (78.5 g, 1.0 mol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The solid was filtered off and the filtrate was concentrated to give 1- (2,3-dihydro-indol-1-yl) -ethanone (82 g, 100%).

(1- (5-Bromo-2,3-dihydro-indol-1-yl) -ethanone)
To a solution of 1- (2,3-dihydro-indol-1-yl) -ethanone (58.0 g, 0.36 mol) in acetic acid (3000 mL) was added Br ₂ (87.0 g, 0.54 mol). Added at 10 ° C. The mixture was stirred at room temperature for 4 hours. The precipitate was collected by filtration to give crude 1- (5-bromo-2,3-dihydro-indol-1-yl) -ethanone (100 g, 96%), which was used directly in the next step. did.

(5-Bromo-2,3-dihydro-1H-indole)
A mixture of 1- (5-bromo-2,3-dihydro-indol-1-yl) -ethanone (100 g, 0.34 mol) in HCl (20%, 1200 mL) was heated to reflux for 6 hours. The mixture was basified with Na2CO3 to pH 8.5-10 and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 5-bromo-2,3-dihydro-1H-indole (37 g, 55%).

(5-Bromo-6-nitro-2,3-dihydro-1H-indole)
Of 5-bromo-2,3-dihydro -1H- indole _{(45g, 0.227mol), H 2} SO 4 (98%, 200mL) was added _in, KNO 3 and (23.5g, 0.23mol) 0 Slowly added at ° C. After the addition, the mixture was stirred at 0-10 ° C. for 4 hours, poured carefully into ice, basified to pH 8 with Na ₂ CO ₃ and extracted with ethyl acetate. The combined courage extracts were washed with brine, dried over Na 2 SO 4 and concentrated to dry lake. The residue was purified by column chromatography on silica gel to give 5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, 76%).

(5-Bromo-6-nitro-1H-indole)
To a solution of 5-bromo-6-nitro-2,3-dihydro-1H-indole (20 g, 82.3 mmol) in 1,4-dioxane (400 mL) was added DDQ (30 g, 0.13 mol). . The mixture was stirred at 80 degrees for 2 hours. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give 5-bromo-6-nitro-1H-indole (7.5 g, 38%).

(B-27; 5-bromo-1H-indol-6-ylamine)
A mixture of 5-bromo-6-nitro-1H-indole (73.5 g, 31.1 mmol) and Raney Ni (1 g) in ethanol was stirred for 2 hours at room temperature with H2 (1 atm). The catalyst was filtered off and the filtrate was concentrated over. The residue was purified by column chromatography on silica gel to give 5-bromo-1H-indol-6-ylamine (B-27) (2 g, 30%).

(7-substituted 6-aminoindole)

(3-Methyl-2,6-dinitro-benzoic acid)
To a mixture of HNO ₃ (95%, 80 mL) and H ₂ SO ₄ (98%, 80 mL), 3-methylbenzoic acid (50 g, 0.37 mol) was slowly added at 0 ° C. After the addition, the mixture was stirred for 1.5 hours while maintaining the temperature below 30 ° C. The mixture was poured into ice water and stirred for 15 minutes. The precipitate was collected by filtration and washed with water to give a mixture of 3-methyl-2,6-dinitro-benzoic acid and 5-methyl-2,4-dinitro-benzoic acid (70 g, 84 $). ) To a solution of this mixture in EtOH (150 mL), SoCl ₂ (53.5 g, 0.45 mol) was added dropwise. The mixture was heated to reflux for 2 hours and concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 10% Na ₂ CO ₃ solution (120 mL). The organic layer was found to contain 5-methyl-2,4-dinitro-benzoic acid ethyl ester. The aquatic is acidified with HCl to pH 2-3 and the resulting precipitate is collected by filtration, washed with water and dried in air to give 3-methyl-2,6-dinitro-benzoic acid. (39 g, 47%) was obtained.

(3-methyl-2,6-dinitro-benzoic acid ethyl ester)
A mixture of 3-methyl-2,6-dinitro-benzoic acid (39 g, 0.15 mol) and SOCl ₂ (80 mL) was heated to reflux for 4 hours. Excess SOCl ₂ was removed under reduced pressure and the residue was added dropwise to a solution of EtOH (100 mL) and Et ₃ N (50 mL). The mixture was stirred at 20 ° C. for 1 hour and concentrated. The residue was dissolved in EtOAc (100 mL), washed with Na ₂ CO ₃ (10%, 40 mL × 2), water (50 mL × 2) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated. There was obtained 3-methyl-2,6-dinitro-benzoic acid ethyl ester (20 g, 53%).

(3- (2-Dimethylamino-vinyl) -2,6-dinitro-benzoic acid ethyl ester)
A mixture of 3-methyl-2,6-dinitro-benzoic acid ethyl ester (35 g, 0.14 mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL) at 100 ° C. for 5 hours. Heated. The mixture was poured into ice water and the precipitate was collected by filtration and washed with water to give 3- (2-dimethylamino-vinyl) -2,6-dinitro-benzoic acid ethyl ester (25 g 58%).

(B-19; 6-amino-1H-indole-7-carboxylic acid ethyl ester)
A mixture of 3- (2-dimethylamino-vinyl) -2,6-dinitro-benzoic acid ethyl ester (30 g, 0.097 mol) and Raney Ni (10 g) in EtOH (1000 mL) under H2 (50 psi). For 2 hours. The catalyst was filtered off and the filtrate was concentrated to dry lake. The residue was generated by column chromatography on silica gel to give 6-nitro-1H-indole-7-carboxylic acid ethyl ester (B-19) as an off-white solid (3.2 g, 16% ).

(Phenol)
Example 1

(2-tert-butyl-5-nitroaniline)
To a cold solution of sulfuric acid (90%, 50 mL) was added 2-tert-butyl-phenylamine (4.5 g, 30 mmol) dropwise at 0 ° C. Potassium nitrate (4.5 g, 45 mmol) was added in portions at 0 ° C. The reaction mixture was stirred at 0-5 ° C. for 5 minutes, poured into ice water and then extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ . After removal of the solvent, the residue was purified by recrystallization using 70% EtOH—H ₂ O to give 2-tert-butyl-5-nitroaniline (3.7 g, 64%).

(C-1-a; 2-tert-butyl-5-nitrophenol)
To a mixture of 2-tert-butyl-5-nitroaniline (1.94 g, 10 mmol) in 40 mL of 15% H ₂ SO ₄ was added a solution of NaNO ₂ (763 mg, 11.0 mmol) in water (3 mL). At 0 ° C. The resulting mixture was stirred at 0-5 ° C. for 5 minutes. Excess NaNO ₂ was neutralized with urea, then 5 mL of H ₂ SO ₄ —H ₂ O (v / v 1: 2) was added and the mixture was refluxed for 5 minutes. The reaction mixture was cooled to room temperature and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-5-nitrophenol (C-1-a) (1.2 g, 62%).

(C-1; 2-tert-butyl-5-aminophenol)
To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), then 140 mg of 10% Pd-C was added. The reaction mixture was refluxed for an additional 30 minutes, cooled to room temperature, and filtered through a plug of celite. The filter station was concentrated to dryness and purified by column chromatography (20-30% EtOAc-hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87% ).

(Example 2)
General scheme:

Concrete example:

(1-tert-butyl-2-methoxy-4-nitrobenzene)
To a mixture of 2-tert-butyl-5-nitrophenol (C-1-a) (100 mg, 0.52 mmol) and K ₂ CO ₃ (86 mg, 0.62 mmol) in DMF (2 mL) was added CH ₃ I. (40 μL, 0.62 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ , after filtration, the filtrate was evaporated to dryness to give 1-tert-butyl-2methoxy-4-nitrobenzene (82 g, 76% ), Which was used without further purification.

(C-2; 4-tert-butyl-3-methoxyaniline)
To a refluxing solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 0.4 mmol) in EtOH (200 mL) was added potassium formate (300 mg, 3.6 mmol) in water (1 mL). This was followed by the addition of 10% Pd-C (15 mg). The reaction mixture was refluxed for an additional 60 minutes, cooled to room temperature, and filtered through celite. The filtrate was concentrated to dryness to give 4-tert-butyl-3-methoxyaniline (C-2) (52 mg, 72%), which was used without further purification. Time HPLC retention k of 2.29 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 180.0m / z ( MH +).

  Other examples:

(C-3; 3- (2-ethoxyethoxy) -4-tert-butylbenzenamine)
3- (2-Ethoxyethoxy) -4-tert-butylbenzenamine (C-3) with 2-tert-butyl-5-nitrophenol (C-1-a) and 1-bromo-2-ethoxyethane Starting and synthesized according to the general scheme above.

(C-4; 2- (2-tert-butyl-5-aminophenoxy) ethanol)
2- (2-tert-butyl-5-aminophenoxy) ethanol (C-4) was started with 2-tert-butyl-5-nitrophenol (C-1-a) and 2-bromoethanol above. Synthesized according to the general scheme. HPLC retention time 2.08 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 210.3m / z ( MH +).

  (Example 3)

(N- (3-hydroxy-phenyl) -acetamide and acetic acid 3-formylamino-phenyl ester)
To a well-stirred suspension of 3-amino-phenol (50 g, 0.46 mol) and NaHCO ₃ (193.2 g, 2.3 mol) in chloroform (1 L) was added chloroacetyl chloride (46.9 g). , 0.6 mol) was added dropwise at 0 ° C. over 10 minutes. After the addition was complete, the reaction mixture was refluxed overnight and then cooled to room temperature. Excess NaHCO ₃ was removed by filtration. The filtrate was poured into water and extracted with EtOAc (300 × 3 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give N- (3-hydroxy-phenyl) -acetamide and 3-formylamino-phenyl acetate. A mixture with the ester was obtained (35 g, 4: 1 by NMR analysis). This mixture was used directly in the next step.

(N- [3- (3-Methyl-but-3-enyloxy) -phenyl] -acetamide)
Mixture of N- (3-hydroxy-phenyl) -acetamide and acetic acid 3-formylamino-phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-1-ol (8.6 g) , 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) were heated to reflux overnight and then cooled to room temperature. . The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300 x 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give N- [3- (3-methyl-but-3-enyloxy) -phenyl] -acetamide (11 g, 52%).

(N- (4,4-Dimethyl-chroman-7-yl) -acetamide)
N- [3- (3-Methyl-but-3-enyloxy) -phenyl] -acetamide (2.5 g, 11.4 mmol) and AlCl3 (4.52 g, 34.3 mmol) in fluoro-benzene (50 mL). The mixture was heated to reflux overnight. After cooling, the reaction mixture was poured into water. The organic layer was separated and the aqueous phase was extracted with EtOAc (40 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give N- (4,4-dimethyl-chroman-7-yl) -acetamide (1.35 g, 54%).

(C-5; 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine)
A mixture of N- (4,4-dimethyl-chroman-7-yl) -acetamide (1.35 g, 6.2 mmol) in 20% HCl solution (30 mL) was heated to reflux for 3 hours and then allowed to reach room temperature. Cooled down. The reaction mixture was basified with 10% aqueous NaOH to pH 8 and extracted with EtOAc (30 × 3 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5). (1 g, 92%).

Example 4
General scheme:

Concrete example

(2-tert-butyl-4-fluorophenol)
4- fluorophenol (5 g, 45 mmol) and tert- butanol (5.9 mL, 63 mmol) _was dissolved in CH ₂ Cl ₂ (80mL), and concentrated sulfuric acid (98%, 3 mL) and treated with. The mixture was stirred overnight at room temperature. The organic layer was washed with water, neutralized with NaHCO ₃ , dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (5-15% EtOAc-hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42%).

(2-tert-butyl-4-fluorophenylmethyl carbonate)
To a solution of 2-tert-butyl-4-fluorophenol (2.63 g, 15.7 mmol) and NEt3 (3.13 mL, 22.5 mmol) in dioxane (45 mL) was added methyl chloroformate (1.27 mL, 16 0.5 mmol) was added. The mixture was stirred at room temperature for 1 hour. The precipitate was removed by filtration. The filtrate was then diluted with water and extracted with ether. The ether extract was washed with water and dried over MgSO _4. After removal of the solvent, the residue was purified by column chromatography to give 2-tert-butyl-4-fluorophenylmethyl carbonate. (2.08 g, 59%).

(2-tert-butyl-4-fluoro-5-nitrophenylmethyl carbonate (C-7-a) and 2-tert-butyl-4-fluoro-6-nitrophenylmethyl carbonate (C-6-a))
To a solution of 2-tert-butyl-4-fluorophenylmethyl carbonate (1.81 g, 8 mmol) in H ₂ SO ₄ (98%, 1 mL) was added H ₂ SO ₄ (1 mL) and HNO ₃ (1 mL). The cold mixture was added slowly at 0 ° C. The mixture was stirred for 2 hours while warming to room temperature, poured onto ice and extracted with diethyl ether. The ether extract was washed with brine, dried over MgSO 4 and concentrated. The residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-4-fluoro-5-nitrophenylmethyl carbonate (C-7-a) (1.2 g, 55 %) And 2-tert-butyl-4-fluoro-6-nitrophenylmethyl (C-6-a) carbonate (270 mg, 12%). 2-tert-butyl-4-fluoro-5-nitrophenylmethyl carbonate (C-7-a): δ 8.24 (d, J = 7.1 Hz, 1H), 7.55 (d, J = 13.4 Hz) , 1H), 3.90 (s, 3H), 1.32 (s, 9H). 2-tert-butyl-4-fluoro-6-nitrophenylmethyl carbonate (C-6-a):

(2-tert-butyl-4-fluoro-5-nitrophenol)
To a solution of 2-tert-butyl-4-fluoro-5-nitrophenylmethyl carbonate (C-7-a) (1.05 g, 4 mmol) in CH ₂ Cl ₂ (40 mL) was added piperidine (3.94 mL, 10 mmol) was added. The mixture was stirred at room temperature for 1 hour and extracted with 1N NaOH (3 ×). The aqueous layer was acidified with 1N HCl and extracted with diethyl ether. The ether extract was washed with brine, dried (MgSO ₄ ) and concentrated to give 2-tert-butyl-4-fluoro-5-nitrophenol (530 mg, 62%).

(C-7; 2-tert-butyl-5-amino-4-fluorophenol)
To a refluxing solution of 2-tert-butyl-4-fluoro-5-nitrophenol (400 mg, 1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 mL) was added 5% Pd-C (260 mg ) Was added. The mixture was refluxed for an additional hour, cooled and filtered through celite. The solvent was removed by evaporation to give 2-tert-butyl-5-amino-4-fluorophenol (C-7) (550 mg, 83%).

Other examples:

(C-10; 2-tert-butyl-5-amino-4-chlorophenol)
2-tert-butyl-5-amino-4-chlorophenol (C-10) was synthesized according to the above general scheme starting with 4-chlorophenol and tert-butanol. Overall yield (6%). HPLC retention time 3.07 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 200.2m / z ( MH +).

(C-13; 5-amino-4-fluoro-2- (1-methylcyclohexyl) phenol)
5-Amino-4-fluoro-2- (1-methylcyclohexyl) phenol (C-13) was synthesized according to the above general scheme starting with 4-fluorophenol and 1-methylcyclohexanol. Overall yield (3%). HPLC retention time 3.00 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 224.2m / z ( MH +).

(C-19; 5-amino-2- (3-ethylpentan-3-yl) -4-fluoro-phenol)
Starting with 5-amino-2- (3-ethylpentan-3-yl) -4-fluoro-phenol (C-19) with 4-fluorophenol and 3-ethyl-3-pentanol, the above general scheme Was synthesized according to Overall yield (1%).

(C-20; 2-adamantyl-5-amino-4-fluoro-phenol)
2-adamantyl-5-amino-4-fluoro-phenol (C-20) was synthesized according to the above general scheme starting with 4-fluorophenol and adamantan-1-ol.

(C-21; 5-amino-4-fluoro-2- (1-methylcycloheptyl) phenol)
5-Amino-4-fluoro-2- (1-methylcycloheptyl) phenol (C-21) was synthesized according to the above general scheme starting with 4-fluorophenol and 1-methyl-cycloheptanol.

(C-22; 5-amino-4-fluoro-2- (1-methylcyclooctyl) phenol)
5-Amino-4-fluoro-2- (1-methylcyclooctyl) phenol (C-22) was synthesized according to the above general scheme starting with 4-fluorophenol and 1-methyl-cyclooctanol.

(C-23; 5-amino-2- (3-ethyl-2,2-dimethylpentan-3-yl) -4-fluoro-phenol)
5-amino-2- (3-ethyl-2,2-dimethylpentan-3-yl) -4-fluoro-phenol (C-23) was converted to 4-fluorophenol and 3-ethyl-2,2-dimethyl- Synthesized according to the above general scheme starting with pentan-3-ol.

  (Example 5)

(C-6; 2-tert-butyl-4-fluoro-6-aminophenylmethyl carbonate)
To a refluxing solution of 2-tert-butyl-4-fluoro-6-nitrophenylmethyl carbonate (250 mg, 0.92 mmol) and ammonium formate (250 mg, 4 mmol) in EtOH (10 mL) was added 5% Pd-C (170 mg). ) Was added. The mixture was refluxed for an additional hour, cooled and filtered through celite. The solvent was removed by evaporation and the residue was purified by column chromatography (0-15%, EtOAc-hexanes) to give 2-tert-butyl-4-fluoro-6-aminophenylmethyl carbonate (C -6) was obtained (60 mg, 27%). HPLC retention time 3.35 minutes, the implementation of _10~99% CH 3 CN, 5 min, ESI-MS 242.0m / z ( MH +).

  (Example 6)

(Carbonate 2,4-di-tert-butyl-phenyl ester methyl ester)
Methyl chloroformate (58 mL, 750 mmol) was cooled to 0 ° C. in an ice-water bath with 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et ₃ N (139 mL, 1000 mmol) and DMAP. (3.05 g, 25 mmol) was added dropwise to a solution in dichloromethane (400 mL). The mixture was allowed to warm to room temperature with stirring overnight, then filtered through silica gel (about 1 L) using 10% ethyl acetate-hexane (about 4 L) as eluent. The combined filtrate was concentrated to give carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g, quantitative).

(Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester)
To a stirred solution of 2,4-di-tert-butyl-phenyl ester methyl carbonate (4.76 g, 18 mmol) in concentrated sulfuric acid (2 mL), while cooling in an ice-water bath, sulfuric acid (2 mL) and nitric acid ( 2 mL) of the cold mixture was added. This addition was performed slowly so that the reaction temperature did not exceed 50 ° C. The reaction was stirred for 2 hours while warming to room temperature. The reaction mixture was then added to ice water and extracted into diethyl ether. The ether layer was dried (MgSO ₄ ), concentrated and purified by column chromatography (0-10% ethyl acetate-hexane) to give 2,4-di-tert-butyl-5-nitro-phenyl ester methyl carbonate. The ester and carbonate 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester were obtained as a pale yellow solid (4.28 g), which was used directly in the next step.

(2,4-di-tert-butyl-5-nitro-phenol and 2,4-di-tert-butyl-6-nitro-phenol)
Mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester (4.2 g, 12.9 mmol ) Was dissolved in MeOH (65 mL) and KOH (2.0 g, 36 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was then approved (pH 2-3) by adding concentrated HCl and partitioned between water and diethyl ether. The ether layer was dried (MgSO ₄ ), concentrated and purified by column chromatography (0-5% ethyl acetate-hexane) to give 2,4-di-tert-butyl-5-nitro-phenol (1 .31 g, 29% over 2 steps) and 2,4-di-tert-butyl-6-nitro-phenol. 2,4-di-tert-butyl-5-nitro-phenol: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1 H, OH), 7.64 (s, 1 H), 6.83 (S, 1H), 1.36 (s, 9H), 1.30 (s, 9H). 2,4-di-tert-butyl-6-nitro-phenol:

(C-9; 5-amino-2,4-di-tert-butyl-phenol)
To a refluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.4 mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5 wt. % (900 mg) was added. The reaction mixture was stirred at reflux for 2 hours, cooled to room temperature, and filtered through celite. The celite was washed with methanol and the combined filtrates were concentrated to give 5-amino-2,4-di-tert-butyl-phenol as a gray solid (1.66 g, quantitative).

(C-8; 6-amino-2,4-di-tert-butyl-phenol)
A solution of 5-amino-2,4-di-tert-butyl-nitro-phenol (27 mg, 0.11 mmol) and SnCl ₂ .2H ₂ O (121 mg, 0.54 mmol) in EtOH (1.0 mL). And heated in a microwave oven at 100 ° C. for 30 seconds. The mixture was diluted with EtOAc and water, basified with saturated NaHCO ₃ and filtered through celite. The organic layer was separated and dried over Na ₂ SO ₄ , the solvent was removed by evaporation to give 6-amino-2,4-di-tert-butyl-phenol (C-8), which Was used without further purification. HPLC retention time 2.74 minutes, the implementation of _10~99% CH 3 CN, 5 ^{min; ESI-MS222.5m / z (MH} +).

  (Example 7)

(4-tert-butyl-2-chloro-phenol)
To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and SO ₂ Cl ₂ (37.5 g, 0.28 mol) in CH ₂ Cl ₂ was added MeOH (9.0 g, 0.28 mol). ) Was added at 0 ° C. After the addition was complete, the mixture was stirred at room temperature overnight and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / EtOAc, 50: 1) to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95%).

(4-tert-butyl-2-chlorophenylmethyl carbonate)
To a solution of 4-tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) in dichloromethane (200 mL) was added Et ₃ N (50.5 g, 0.50 mol), DMAP (1 g) and chloroformate. Methyl (35.4 g, 0.38 mol) was added at 0 ° C. The reaction was warmed to room temperature and stirred for an additional 30 minutes. The reaction mixture was washed with H 2 O and the organic layer was dried over Na ₂ SO ₄ and concentrated to give 4-tert-butyl-2-chlorophenylmethyl carbonate (56.6 g, 92%), This was used directly in the next step.

(4-tert-butyl-2-chloro-5-nitrophenylmethyl carbonate)
Carbonate 4-tert-butyl-2-chlorophenyl methyl (36.0 g, 0.15 mol) and of concentrated _H 2 _SO 4 (100mL), was dissolved at 0 ° C.. KNO3 (0.53 g, 5.2 mmol) was added in portions over 20 minutes. The reaction mixture was stirred for 1.5 hours and poured onto ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with aqueous NaHCO?, Dried over _Na 2 SO _4, and concentrated in vacuo to give a carbonate 4-tert-butyl-2-chloro-5-nitrophenyl methyl (41.0 g ), Which was used without further purification.

(4-tert-butyl-2-chloro-5-nitro-phenol)
Potassium hydroxide (10.1 g, 181 mmol) was added to 4-tert-butyl-2-chloro-5-nitrophenylmethyl carbonate (40.0 g, 139 mmol) in MeOH (100 mL). After 30 minutes, the reaction was acidified with 1N HCl and extracted with chloromethane. The combined organic layers were combined, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude residue was purified by column chromatography (petroleum ether / EtOAc, 30: 0) to give 4-tert-butyl-2-chloro-5-nitro-phenol (23.0 g, 68 over 2 steps). %).

(C-11; 4-tert-butyl-2-chloro-5-amino-phenol)
To a solution of 4-tert-butyl-2-chloro-5-nitro-phenol (12.6 g, 54.9 mmol) in MeOH (50 mL) was added Ni (1.2 g). The reaction was shaken under H ₂ (1 atm) for 4 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (PE / EtOAc, 20: 1) to give 4-tert-butyl-2-chloro-5-amino-phenol (C-11) (8. 5 g, 78%).

(Example 8)

(2-adamantyl-4-methyl-phenylethyl carbonate)
Ethyl chloroformate (0.64 mL, 6.7 mmol) was added 2-adamantyl-4-methylphenol (1.09 g, 4.5 mmol), Et in dichloromethane (8 mL) cooled to 0 ° C. in an ice-water bath. _{It was} added dropwise to a solution of 3N (1.25 mL, 9 mmol) and DMAP (catalytic amount). The mixture was allowed to warm to room temperature with stirring overnight, then filtered and the filtrate concentrated. The residue was purified by column chromatography (10-20% ethyl acetate-hexane) to give 2-adamantyl-4-methyl-phenylethyl carbonate as a yellow oil (1.32 g, 94%).

(2-adamantyl-4-methyl-5-nitrophenylethyl carbonate)
To a cooled solution of 2-adamantyl-4-methyl-phenylethyl carbonate (1.32 g, 4.2 mmol) in H ₂ SO ₄ (98%, 10 mL) was added KNO ₃ (510 mg, 5.0 mmol) at 0 ° C. Was added in small portions. The mixture was stirred for 3 hours while warming to room temperature, poured onto ice and then extracted with dichloromethane. The combined organic layers were washed with NaHCO ₃ and brine, dried over MgSO ₄ and concentrated to dryness. The residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-adamantyl-4-methyl-5-nitrophenylethyl carbonate (378 mg, 25%).

(2-adamantyl-4-methyl-5-nitrophenol)
To a solution of 2-adamantyl-4-methyl-5-nitrophenylethyl carbonate (378 mg, 1.05 mmol) in CH ₂ Cl ₂ (5 mL) was added piperidine (1.0 mL). The solution was stirred at room temperature for 1 hour, adsorbed onto silica gel under reduced pressure, and purified by flash chromatography on silica gel (0-15%, EtOAc-hexane) to give 2-adamantyl-4-methyl-5. -Nitrophenol was obtained (231 mg, 77%).

(C-12; 2-adamantyl-4-methyl-5-aminophenol)
To a solution of 2-adamantyl-4-methyl-5-nitrophenol (231 mg, 1.6 mmol) in EtOH (2 mL) was added Pd-5 wt% (10 mg) on carbon. The mixture was stirred overnight under H ₂ (1 atm) and then filtered through celite. The filtrate was evaporated to dryness to give 2-adamantyl-4-methyl-5-aminophenol (C-12), which was used without further purification. HPLC retention time 2.52 min, implementation of _10~99% CH 3 CN, 5 min; ESI-MS 258.3m / z ( MH +).

  Example 9

(2-tert-butyl-4-bromophenol)
2-tert-butylphenol (250 g, 1.67 mol) in _a solution in CH 3 CN (1500mL), and NBS to (300 g, 1.67 mol) was added at room temperature. After the addition, the mixture was stirred overnight at room temperature and then the solvent was removed. Petroleum ether (1000 mL) was added and the resulting white precipitate was filtered off. The filtrate was concentrated under reduced pressure to give crude 2-tert-butyl-4-bromophenol (380 g), which was used without further purification.

(Methyl carbonate (2-tert-butyl-4-bromophenyl))
To a solution of 2-tert-butyl-4-bromophenol (380 g, 1.67 mol) in dichloromethane (1000 mL) was added Et ₃ N (202 g, 2 mol) at room temperature, methyl chloroformate (155 mL) was added. It was dripped at the upper part of this solution at 0 degreeC. After the addition, the mixture was stirred at 0 ° C. for 2 hours, quenched with saturated ammonium chloride solution and diluted with water. The organic layer was separated and washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give crude methyl carbonate (2-tert-butyl-4-bromophenyl) (470 g) which Was used without further purification.

(Methyl carbonate (2-tert-butyl-4-bromo-5-nitrophenyl))
Methyl carbonate (2-tert-butyl-4-bromophenyl) (470 g, 1.49 mol) was dissolved in concentrated H ₂ SO ₄ (1000 ml) at 0 ° C. KNO ₃ (253 g, 2.5 mol) was added dropwise over 90 minutes. The reaction mixture was stirred at 0 ° C. for 2 hours and poured into ice water (20 L). The resulting precipitate is collected by filtration and washed thoroughly with water, dried and recrystallized from ether to give methyl carbonate (2-tert-butyl-4-bromo-5-nitrophenyl). Obtained (332 g, 60% over 3 steps).

(C-14-a; 2-tert-butyl-4-bromo-5-nitro-phenol)
To a solution of methyl carbonate (2-tert-butyl-4-bromo-5-nitrophenyl (121.5 g, 0.366 mol) in methanol (1000 mL) is added potassium hydroxide (30.75 g, 0.549 mol). After the addition, the mixture was stirred at room temperature for 3 hours and acidified with 1N HCl to pH 7. Methanol was removed and water was added The mixture was extracted with ethyl acetate and organic The layers were separated, dried over Na ₂ SO ₄ and concentrated to give 2-tert-butyl-4-bromo-5-nitro-phenol (C-14-a) (100 g, 99%).

(1-tert-butyl-2- (benzyloxy) -5-bromo-4-nitrobenzene)
2-tert-butyl-4-bromo-5-nitro - phenol (C-14-a) ( 1.1g, 4mmol) and _{Cs 2 CO 3 (1.56g, 4.8mmol} ), in DMF (8 mL) To the mixture was added benzyl bromide (500 μL, 4.2 mmol). The mixture was stirred at room temperature for 4 hours, diluted with H.sub.2O and extracted twice with EtOAc. The combined organic layers were washed with water and dried over MgSO4. After removal of the solvent, the residue was purified by column chromatography (1-5% EtOAc-hexane) to give 1-tert-butyl-2. -(Benzyloxy) -5-bromo-4-nitrobenzene was obtained (1.37 g, 94%).

(1-tert-butyl-2- (benzyloxy) -5- (trifluoromethyl) -4-nitrobenzene)
1-tert-butyl-2- (benzyloxy) -5-bromo-4-nitrobenzene (913 mg, 2.5 mmol), KF (291 mg, 5 mmol), KBr (595 mg, 5 mmol), CuI (570 mg, 3 mmol), chloro A mixture of methyl difluoroacetate (1.6 mL, 15 mmol) and DMF (5 mL) was stirred overnight at 125 ° C. in a sealed tube, cooled to room temperature, diluted with water, and extracted three times with EtOAc. . The combined organic layers were washed with brine and dried over anhydrous MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography (0-5% EtOAc-hexane) to give 1-tert-butyl-2- (benzyloxy) -5- (trifluoromethyl) -4- Nitrobenzene was obtained (591 mg, 67%).

(C-14; 5-amino-2-tert-butyl-4-trifluoromethyl-phenol)
Reflux of 1-tert-butyl-2- (benzyloxy) -5- (trifluoromethyl) -4-nitrobenzene (353 mg, 1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 mL). To the solution was added 10% Pd-C (245 mg). The mixture was refluxed for a further 2 hours, cooled to room temperature and filtered through celite. After removal of the solvent, the residue was purified by column chromatography to give 5-amino-2-tert-butyl-4-trifluoromethyl-phenol (C-14) (120 mg, 52%).

(Example 10)
General scheme:

Concrete example:

(2-tert-butyl-4- (2-ethoxyphenyl) -5-nitrophenol)
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30 mmol) in DMF (90 mL) was added 2-ethoxyphenylboronic acid (5.48 g, 33 mmol), potassium carbonate (4.56 g, 33 mmol), water (10 ml) and Pd (PPh ₃ ) ₄ (1.73 g, 1.5 mmol) were added. The mixture was heated at 90 degrees for 3 hours under nitrogen. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether-ethyl acetate, 10: 1) to give 2-tert-butyl-4- (2-ethoxyphenyl) -5. -Nitrophenol was obtained (9.2 g, 92%).

(C-15; 2-tert-butyl-4- (2-ethoxyphenyl) -5-aminophenol)
Raney Ni (300 mg) was added to a solution of 2-tert-butyl-4- (2-ethoxyphenyl) -5-nitrophenol (3.0 g, 9.5 mmol) in methanol (30 ml). The mixture was stirred at room temperature under H ₂ (1 atm) for 2 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-ethyl acetate, 6: 1) to give 2-tert-butyl-4- (2-ethoxyphenyl) -5-aminophenol (C-15). (2.35 g, 92%).

Other examples:

(C-16; 2-tert-butyl-4- (3-ethoxyphenyl) -5-aminophenol)
2-tert-butyl-4- (3-ethoxyphenyl) -5-aminophenol (C-16) was converted to 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3- Synthesized according to the above general scheme starting with ethoxyphenylboronic acid. HPLC retention time 2.77 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS
286.1 m / z (MH ⁺ ).

(C-17; 2-tert-butyl-4- (3-methoxycarbonylphenyl) -5-aminophenol (C-17))
2-tert-butyl-4- (3-methoxycarbonylphenyl) -5-aminophenol (C-16) was converted to 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3 Synthesized according to the general scheme above starting with-(methoxycarbonyl) phenylboronic acid. HPLC retention time 2.70 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 300.5m / z ( MH +).

  (Example 11)

(1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene)
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and Cs2CO3 (2.2 g, 6.6 mmol) in DMF (6 mL) was added methyl iodide (5150 μL, 8 .3 mmol) was added. The mixture was stirred at room temperature for 4 hours, diluted with H.sub.2O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After removal of the solvent, the residue was washed with hexane to give 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, 69%).

(1-tert-butyl-2-methoxy-5- (trifluoromethyl) -4-nitrobenzene)
1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0 mmol), KF (348 mg, 6 mmol), KBr (714 mg, 6 mmol), CuI (684 mg, 3.6 mmol), chlorodifluoro A mixture of methyl acetate (2.2 mL, 21.0 mmol) in DMF (5 mL) was stirred at 125 ° C. in a sealed tube overnight, cooled to room temperature, diluted with water, and EtOAc. Extracted 3 times. The combined organic layers were washed with brine and dried over anhydrous MgSO _4. After removal of the solvent, the residue was purified by column chromatography (1-5% EtOAc-hexane) to give 1-tert- Butyl-2-methoxy-5- (trifluoromethyl) -4-nitrobenzene was obtained (512 mg, 61%).

(C-18; 1-tert-butyl-2-methoxy-5- (trifluoromethyl) -4-aminobenzene)
To a refluxing solution of 1-tert-butyl-2-methoxy-5- (trifluoromethyl) -4-nitrobenzene (473 mg, 1.7 mmol) and ammonium formate (473 mg, 7.3 mmol) in EtOH (10 mL) was added. 10% Pd-C (200 mg) was added. The mixture was refluxed for 1 hour, cooled, and filtered through celite. The solvent was removed by evaporation to give 1-tert-butyl-2-methoxy-5- (trifluoromethyl) -4-nitrobenzene (C-18) (403 mg, 95%).

(Example 12)

(C-27; 2-tert-butyl-4-bromo-5-amino-phenol)
To a solution of 2-tert-butyl-4-bromo-5-nitro-phenol (C-14-a) (12 g, 43.8 mmol) in MeOH (90 mL) was added Ni (2.4 g). The reaction mixture was stirred under H ₂ (1 atm) for 4 hours. The mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from ethyl acetate and petroleum ether to give 2-tert-butyl-4-bromo-5-amino-phenol (C-27) (7.2 g, 70%).

(Example 13)

(C-24; 2,4-di-tert-butyl-6- (N-methylamino) phenol)
Of 2,4-di-tert-butyl-6-amino-phenol (C-9) (5.08 g, 23 mmol), NaBH ₃ CH (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol), The mixture in methanol (50 mL) was stirred under reflux conditions for 3 hours. After removal of the solvent, the residue was purified by column chromatography (petroleum ether-EtOAc, 30: 1) to give (C-24) (8800 mg, 15%).

(Example 14)

(2-methyl-2-phenyl-propan-1-ol)
To a solution of 2-methyl-2-phenyl-propionic acid (82 g, 0.5 mol) in THF (200 mL) was added dropwise borane-dimethyl sulfide (2M, 100 mL) at 0-5 ° C. The mixture was stirred at this temperature for 30 minutes and then heated to reflux for 1 hour. After cooling, methanol (150 mL) and water (50 mL) were added. The mixture was extracted with EtOAc (100 mL × 3) and the combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to 2-methyl-2-phenyl-propane-1 The ol was obtained as an oil (70 g, 77%).

(2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -benzene)
To a suspension of NaH (29 g, 0.75 mol) in THF (200 mL) was added 2-methyl-2-phenyl-propan-1-ol (75 g, 0.5 mol) in THF (50 mL) at 0 ° C. The solution was added dropwise. The mixture was stirred at 20 ° C. for 30 minutes, then a solution of 1-bromo-2-methoxy-ethane (104 g, 0.75 mol) in THF (100 mL) was added dropwise at 0 ° C. The mixture was stirred at 20 ° C. overnight, poured into water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -benzene as an oil (28 g, 27%).

(1- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -4-nitro-benzene)
To a solution of 2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -benzene (52 g, 0.25 mol) in CHCl ₃ (200 mL), KNO ₃ (50.5 g, 0.5 mol) and TMSCL (54 g, 0.5 mol) was added. The mixture was stirred at 20 ° C. for 30 minutes and then AlCl ₃ (95 g, 0.7 mol) was added. The reaction mixture was stirred at 20 ° C. for 1 hour and poured into ice water. The organic layer was separated and the aqueous layer was extracted with CHCl ₃ (50 mL × 3). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether) to give 1- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -4-nitro-benzene (6 g, 10%). Obtained.

(4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenylamine)
Suspension of 1- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -4-nitro-benzene (8.1 g, 32 mmol) and Raney Ni (1 g) in MeOH (50 mL). Was stirred under H ₂ (1 atm) for 1 hour at room temperature. The catalyst was filtered off and the filtrate was concentrated to give 4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenylamine (5.5 g, 77%).

(4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -3-nitro-phenylamine)
To a solution of 4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenylamine (5.8 g, 26 mmol) in H ₂ SO ₄ (20 mL) at 0 ° C. with KNO _3. (2.63 g, 26 mmol) was added. After the addition was complete, the mixture was stirred at this temperature for 20 minutes and then poured into ice water. This mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100: 1) to give 4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -3-nitro-phenylamine (5 g 71%).

(N- {4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -3-nitro-phenyl} -acetamide)
To a suspension of NaHCO ₃ (10 g, 0.1 mol) in dichloromethane (50 mL) was added 4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -3 at 0-5 ° C. -Nitro-phenylamine (5 g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) were added. The mixture was stirred at 15 ° C. overnight and then poured into water (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness to give N- [4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl]. -3-Nitro-phenyl} -acetamide (5.0 g, 87%) was obtained.

(N- {3-amino-4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenyl} -acetamide)
N- {4- [2- (2-Methoxy-ethoxy) -1,1-dimethyl-ethyl] -3-nitro-phenyl} -acetamide (5 g, 16 mmol) and Raney Ni (1 g) in MeOH (50 mL). Was stirred for 1 hour at room temperature under H ₂ (1 atm). The catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100: 1) to give N- {3-amino-4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenyl. } -Acetamide (1.6 g, 35%) was obtained.

(N- {3-hydroxy-4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenyl} -acetamide)
N- {3-Amino-4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenyl} -acetamide (1.6 g, H ₂ SO ₄ (15%, 6 mL). 5.7 mmol) solution was added NaNO ₂ at 0-5 ° C. The mixture was stirred at this temperature for 20 minutes and then poured into ice water. This mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 100: 1) to give N- {3-hydroxy-4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenyl. } -Acetamide (0.7 g, 38%) was obtained.

(C-25; 2- (1- (2-methoxyethoxy) -2-methylpropan-2-yl) -5-aminophenol)
A mixture of N- (3-hydroxy-4- [2- (2-methoxy-ethoxy) -1,1-dimethyl-ethyl] -phenyl) -acetamide (1 g, 3.5 mmol) and HCl (5 mL) was added for 1 hour. Over reflux. The mixture was basified with Na ₂ CO ₃ solution to pH 9 and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by column chromatography (petroleum ether-EtOAc, 100: 1) to give 2- (1- (2-methoxyethoxy) -2-methylpropan-2-yl) -5-aminophenol (C-25 ) (61 mg, 6%).

(Example 15 :)

4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione)
To a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g, 19.1 mmol) in acetic acid (115 mL) slowly add HNO ₃ (15 mL). Added. The mixture was heated at 60 ° C. for 40 minutes, after which it was poured into H ₂ O (50 mL). The mixture was allowed to stand at room temperature for 2 hours and then placed in an ice bath for 1 hour. The solid was collected and washed with water to give 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24%).

(4,6-di-tert-butyl-3-nitrobenzene-1,2-diol)
In a separatory funnel, THF / H ₂ O (1: 1, 400 mL), 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (4.59 g, 17.3 mmol) and Na ₂ S ₂ O ₄ (3 g, 17.3 mmol). The separatory funnel was fitted with a stopper and shaken for 2 minutes. The mixture was diluted with EtOAc (20 mL). The layers were separated and the organic layer was washed with brine, dried over MgSO ₄ and concentrated to 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 74 %). This was used without further purification.

(C-26; 4,6-di-tert-butyl-3-aminobenzene-1,2-diol)
To a solution of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (1.92 g, 7.2 mmol) in EtOH (70 mL) was added Pd on carbon (5 wt%) (200 mg). did. The mixture was stirred under H ₂ (1 atm) for 2 hours. The reaction was recharged with Pd on carbon (5 wt%) (200 mg) and stirred for an additional 2 hours under H ₂ (1 atm). The mixture is filtered through Celite and the filtrate is concentrated and purified by column chromatography (10-40% ethyl acetate-hexane) to give 4,6-di-tert-butyl-3-aminobenzene-1, 2-Diol (C-26) (560 mg, 33%) was obtained.

(Aniline)
(Example 1 :)
(General scheme)

(Specific examples :)

(D-1; 4-chloro-benzene-1,3-diamine)
A mixture of 1-chloro-2,4-dinitro-benzene (100 mg, 0.5 mmol) and SnCl ₂ .2H ₂ O (1.12 g, 5 mmol) in ethanol (2.5 mL) was stirred overnight at room temperature. did. Water was added and the mixture was then basified to pH 7-8 with saturated NaHCO ₃ solution. This solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over _Na 2 SO _4, filtered, and concentrated to give 4-chloro - benzene 1,3-diamine (D-1) was obtained (79 mg, quantitative) . HPLC retention time 0.38 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 143.1m / z ( MH +).

  (Other embodiments :)

(D-2; 4,6-dichloro-benzene-1,3-diamine)
4,6-Dichloro-benzene-1,3-diamine (D-2) was synthesized according to the above general scheme starting from 1,5-dichloro-2,4-dinitro-benzene. Yield (95%). HPLC retention time 1.88 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 177.1m / z ( MH +).

(D-3; 4-methoxy-benzene-1,3-diamine)
4-Methoxy-benzene-1,3-diamine (D-3) was synthesized according to the general scheme above starting from 1-methoxy-2,4-dinitro-benzene. Yield (quantitative). HPLC retention time 0.31 minutes, the implementation of _10~99% CH 3 CN, 5 min.

(D-4; 4-trifluoromethoxy-benzene-1,3-diamine)
4-Trifluoromethoxy-benzene-1,3-diamine (D-4) was synthesized according to the general scheme above starting from 2,4-dinitro-1-trifluoromethoxy-benzene. Yield (89%). HPLC retention time 0.91 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 193.3m / z ( MH +).

(D-5; 4-propoxybenzene-1,3-diamine)
4-propoxybenzene-1,3-diamine (D-5) was synthesized according to the general scheme above starting from 5-nitro-2-propoxy-phenylamine. Yield (79%). HPLC retention time 0.54 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 167.5m / z ( MH +).

(Example 2 :)
(General scheme)

(Specific examples :)

(2,4-dinitro-propylbenzene)
Concentrated _H 2 _SO 4 (50mL) solution of propylbenzene (10 g, 83 mmol) and the solution was cooled for 30 minutes at 0 ° C., and concentrated _H 2 _SO 4 (50mL) and fuming _HNO 3 previously cooled to 0 ° C. ( 25 mL) solution was added in portions over 15 minutes. The mixture was stirred at 0 degrees for an additional 30 minutes and then allowed to warm to room temperature. The mixture was poured into ice (200 g) -water (100 mL) and extracted with ether (2 × 100 mL). The combined extracts were washed with H ₂ O (100 mL) and brine (100 mL), dried over MgSO ₄ , filtered and concentrated to give 2,4-dinitro-propylbenzene (15.6 g, 89%). Obtained.

(D-6; 4-propyl-benzene-1,3-diamine)
Ethanol (100 mL) solution of 2,4-dinitro - propylbenzene (2.02 g, 9.6 mmol) _to a solution of was added SnCl 2 (9.9g, 52mmol), followed by addition of concentrated HCl (10 mL) was . The mixture was refluxed for 2 hours, poured into ice water (100 mL) and neutralized with solid sodium bicarbonate. The solution was further basified with 10% NaOH solution to a pH of about 10 and extracted with ether (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO ₄ , filtered and concentrated to 4-propyl-benzene-1,3-diamine (D-6) (1.2 g, 83%). Got. No further purification was required for use in the next step; however, the product was not stable over time.

(Other embodiments :)

(D-7; 4-ethylbenzene-1,3-diamine)
4-Ethylbenzene-1,3-diamine (D-7) was synthesized according to the general scheme described above starting from ethylbenzene. Overall yield (76%).

(D-8; 4-isopropylbenzene-1,3-diamine)
4-Isopropylbenzene-1,3-diamine (D-8) was synthesized according to the general scheme above starting from isopropylbenzene. Overall yield (78%).

(D-9; 4-tert-butylbenzene-1,3-diamine)
4-tert-Butylbenzene-1,3-diamine (D-9) was synthesized according to the general scheme described above starting from tert-butylbenzene. Overall yield (48%).

(Example 3 :)
(General scheme)

(Specific examples :)

(4-tert-butyl-3-nitro-phenylamine)
To a mixture of 4-tert-butyl-phenylamine (10.0 g, 67.01 mmol) dissolved in H ₂ SO ₄ (98%, 60 mL) at 0 ° C. KNO ₃ (8.1 g, 80.41 mmol). Was added slowly. After the addition, the reaction was warmed to room temperature and stirred overnight. The mixture was then poured into ice water and basified to pH 8 with saturated NaHCO ₃ solution. This mixture was extracted several times with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10: 1) to give 4-tert-butyl-3-nitro-phenylamine (10 g, 77%).

(4-tert-Butyl-3-nitro-phenyl) -carbamic acid tert-butyl ester)
A mixture of 4-tert-butyl-3-nitro-phenylamine (4.0 g, 20.6 mmol) and Boc ₂ O (4.72 g, 21.6 mmol) in NaOH (2N, 20 mL) and THF (20 mL). Stir at room temperature overnight. THF was removed under reduced pressure. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic layer was washed with NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to (4-tert-butyl-3-nitro-phenyl) -carbamic acid tert-butyl ester (4.5 g, 74% )

(D-10; (3-amino-4-tert-butyl-phenyl) -carbamic acid tert-butyl ester)
A suspension of (4-tert-butyl-3-nitro-phenyl) -carbamic acid tert-butyl ester (3.0 g, 10.19 mol) and 10% Pd-C (1 g) in MeOH (40 mL) was added. Stir overnight at room temperature under H ₂ (1 atm). After filtration, the filtrate is concentrated and the residue is purified by column chromatography (petroleum ether-EtOAc, 5: 1) to give (3-amino-4-tert-butyl-phenyl) -carbamic acid tert-butyl ester ( D-10) was obtained as a brown oil (2.5 g, 93%).

(Other embodiments :)

(D-11; (3-amino-4-isopropyl-phenyl) -carbamic acid tert-butyl ester)
(3-Amino-4-isopropyl-phenyl) -carbamic acid tert-butyl ester (D-11) was synthesized according to the general scheme above starting from isopropylbenzene. Overall yield (56%).

(D-12; (3-amino-4-ethyl-phenyl) -carbamic acid tert-butyl ester)
(3-Amino-4-ethyl-phenyl) -carbamic acid tert-butyl ester (D-12) was synthesized according to the general scheme above starting from ethylbenzene. Overall yield (64%).

(D-13; (3-amino-4-propyl-phenyl) -carbamic acid tert-butyl ester)
(3-Amino-4-propyl-phenyl) -carbamic acid tert-butyl ester (D-13) was synthesized according to the general scheme above starting from propylbenzene. Overall yield (48%).

  (Example 4 :)

(3-Amino-4-tert-butyl-phenyl) -carbamic acid benzyl ester
A solution of 4-tert-butylbenzene-1,3-diamine (D-9) (657 mg, 4 mmol) and pyridine (0.39 mL, 4.8 mmol) in CH ₂ Cl ₂ / MeOH (12/1, 8 mL). Was cooled to 0 ° C. and a solution of benzyl chloroformate (0.51 mL, 3.6 mmol) in CH ₂ Cl ₂ (8 mL) was added dropwise over 10 minutes. The mixture was stirred at 0 ° C. for 15 minutes and then warmed to room temperature. After 1 h, the mixture was washed with 1M citric acid (2 × 20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a crude (3 -Amino-4-tert-butyl-phenyl) -carbamic acid benzyl ester was obtained as a brown viscous gum (0.97 g). This was used without further purification.

((4-tert-butyl-3-formylamino-phenyl) -carbamic acid benzyl ester)
CH ₂ Cl ₂ (7.5 mL) solution of (3-amino -4-tert-butyl - phenyl) - carbamic acid benzyl ester (0.97 g, 3.25 mmol) and pyridine (0.43 mL, 5.25 mmol) of The solution was cooled to 0 ° C. and formic acid-acetic anhydride (3.5 mmol, formic acid (158 μL, 4.2 mmol, 1.3 eq) and acetic anhydride (0.32 mL) in CH ₂ Cl ₂ (2.5 mL). , 3.5 mmol, 1.1 eq.) Was mixed neat and stirred for 1 hour) was added dropwise over 2 minutes. After the addition was complete, the mixture was allowed to warm to room temperature, whereupon it immediately precipitated the precipitate and the resulting slurry was stirred overnight. The mixture was washed with 1M citric acid (2 × 20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na ₂ SO ₄ ) and filtered. The cloudy mixture precipitated a thin bed of solid on the desiccant, and HPLC analysis indicated that this was the desired formamide. The filtrate was concentrated to about 5 mL and diluted with hexane (15 mL) to precipitate further formamide. The desiccant (Na ₂ SO ₄ ) was slurried with methanol (50 mL), filtered, and the filtrate was combined with the material from the CH ₂ Cl ₂ / hexane recrystallization. The resulting mixture was concentrated to give (4-tert-butyl-3-formylamino-phenyl) -carbamic acid benzyl ester as an off-white solid (650 mg, 50% over 2 steps). ¹ H and ¹³ C NMR (CD ₃ OD) shows this product as a racemic mixture.

(N- (5-amino-2-tert-butyl-phenyl) -formamide)
A 100 mL flask is charged with (4-tert-butyl-3-formylamino-phenyl) -carbamic acid benzyl ester (650 mg, 1.99 mmol), methanol (30 mL) and 10% Pd-C (50 mg) and H _2. Stir for 20 hours under (1 atm). CH ₂ Cl ₂ (5 mL) is added to quench the catalyst, then the mixture is passed through Celite through filter paper and concentrated to remove N- (5-amino-2-tert-butyl-phenyl) -formamide off-white. As a solid (366 mg, 96%). Rotamer by ¹ H and ¹³ C NMR (DMSO-d ₆ ).

(D-14; 4-tert-butyl-N-methyl-benzene-1,3-diamine)
A 100 mL flask was charged with N- (5-amino-2-tert-butyl-phenyl) -formamide (340 mg, 1.77 mmol) and purged with nitrogen. THF (10 mL) was added and the solution was cooled to 0 ° C. A solution of lithium aluminum hydride in THF (4.4 mL, 1M solution) was added over 2 minutes. The mixture was then warmed to room temperature. After 15 hours of reflux, the yellow suspension was cooled to 0 ° C., quenched with water (170 μL), 15% aqueous NaOH (170 μL), and water (510 μL), which were added sequentially, and at room temperature. For 30 minutes. The mixture was filtered through Celite and the filter cake was washed with methanol (50 mL). The combined filtrate was concentrated under reduced pressure to give a grey-brown solid. This solid was partitioned between chloroform (75 mL) and water (50 mL). The organic layer was separated, washed with water (50 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to 4-tert-butyl-N-methyl-benzene-1,3-diamine (D- 14) was obtained as a brown oil. The oil was allowed to settle and solidify (313 mg, 98%).

(Example 5)
(General scheme :)

(Specific examples :)

(2,4-dinitro-propylbenzene)
Concentrated _H 2 _SO 4 (50mL) solution of propylbenzene (10 g, 83 mmol) and the solution was cooled for 30 minutes at 0 ° C., and concentrated _H 2 _SO 4 (50mL) and fuming _HNO 3 previously cooled to 0 ° C. ( 25 mL) of solution was added in portions over 15 minutes. The mixture was stirred at 0 ° C. for an additional 30 minutes and then allowed to warm to room temperature. The mixture was poured into ice (200 g) -water (100 mL) and extracted with ether (2 × 100 mL). The combined extracts were washed with H ₂ O (100 mL) and brine (100 mL), dried over MgSO ₄ , filtered and concentrated to give 2,4-dinitro-propylbenzene (15.6 g, 89%). Obtained.

(4-propyl-3-nitroaniline)
A suspension of 2,4-dinitro-propylbenzene (2 g, 9.5 mmol) in H2O (100 mL) was heated at near reflux and stirred vigorously. Pre-prepared by heating a clear orange-red solution of polysulfide (300 mL (10 eq), sodium sulfide nanohydrate (10.0 g), sulfur powder (2.60 g) and H ₂ O (400 mL)). Was added dropwise over 45 minutes. The reddish brown solution was heated to reflux for 1.5 hours. The mixture was cooled to 0 ° C. and then extracted with ether (2 × 200 mL). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 4-propyl-3-nitroaniline (1.6 g, 93%). This was used without further purification.

((3-Nitro-4-propyl-phenyl) -carbamic acid tert-butyl ester)
4-Propyl-3-nitroaniline (1.69 g, 9.4 mmol) was dissolved in pyridine (30 mL) with stirring. Boc anhydride (2.05 g, 9.4 mmol) was added. The mixture was stirred and heated to reflux for 1 hour, after which the solvent was removed under reduced pressure. The resulting oil was redissolved in CH ₂ Cl ₂ (300 mL) and washed with water (300 mL) and brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude oil containing both monoacylated and bisacylated nitro products was purified by column chromatography (0-10% CH ₂ Cl ₂ -MeOH) to give (3-nitro-4-propyl-phenyl) -Carbamic acid tert-butyl ester (2.3 g, 87%) was obtained.

(Methyl- (3-nitro-4-propyl-phenyl) -carbamic acid tert-butyl ester)
A solution of (3-nitro-4-propyl-phenyl) -carbamic acid tert-butyl ester (200 mg, 0.71 mmol) in DMF (5 mL) was added to Ag ₂ O (1.0 g, 6.0 mmol) followed by Methyl iodide (0.20 mL, 3.2 mmol) was added. The resulting suspension was stirred at room temperature for 18 hours and filtered through a Celite pad. The filter cake was washed with CH ₂ Cl ₂ (10 mL). The filtrate was concentrated under reduced pressure. The crude oil was purified by column chromatography (0-10% CH ₂ Cl ₂ -MeOH) to give methyl- (3-nitro-4-propyl-phenyl) -carbamic acid tert-butyl ester as a yellow oil (110 mg , 52%).

(D-15; (3-amino-4-propyl-phenyl) -methyl-carbamic acid tert-butyl ester)
To a solution of methyl- (3-nitro-4-propyl-phenyl) -carbamic acid tert-butyl ester (110 mg, 0.37 mmol) in EtOAc (10 mL) was added 10% Pd-C (100 mg). The resulting suspension was stirred at room temperature under H ₂ (1 atm) for 2 days. The reaction progress was monitored by TLC. When complete, the reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give (3-amino-4-propyl-phenyl) -methyl-carbamic acid tert-butyl ester (D-15) as a colorless crystalline compound (80 mg, 81%). ESI-MS 265.3 m / z (MH ^<+> ).

  (Other embodiments :)

(D-16; (3-amino-4-ethyl-phenyl) -methyl-carbamic acid tert-butyl ester)
(3-Amino-4-ethyl-phenyl) -methyl-carbamic acid tert-butyl ester (D-16) was synthesized according to the general scheme above starting from ethylbenzene. Overall yield (57%).

(D-17; (3-amino-4-isopropyl-phenyl) -methyl-carbamic acid tert-butyl ester)
(3-Amino-4-isopropyl-phenyl) -methyl-carbamic acid tert-butyl ester (D-17) was synthesized according to the general scheme above starting from isopropylbenzene. Overall yield (38%).

  (Example 6)

(2'-ethoxy-2,4-dinitro-biphenyl)
In a pressure flask, 2-ethoxyphenylboronic acid (0.66 g, 4.0 mmol), KF (0.77 g, 13 mmol), Pd2 (dba) ₃ (16 mg, 0.02 mmol) in THF (5 mL), and 2,4-Dinitro-bromobenzene (0.99 g, 4.0 mmol) was added. The vessel was purged with argon for 1 minute, followed by addition of tri-tert-butylphosphine (0.15 mL, 0.48 mmol, 10% solution in hexane). The reaction vessel was purged with argon for an additional minute, sealed, and heated at 80 ° C. overnight. After cooling to room temperature, the solution was filtered through a Celite plug. The filter cake was rinsed with CH ₂ Cl ₂ (10 mL) and the combined organic extracts were concentrated under reduced pressure to give the crude product 2′-ethoxy-2,4-dinitro-biphenyl (0.95 g, 82%). Got. No further purification was performed.

(2'-ethoxy-2-nitrobiphenyl-4-ylamine)
A clear orange-red solution of polysulfide (120 mL, 7.5 eq) previously prepared by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g) and water (160 mL) was added to water (40 mL). To a suspension of 2′-ethoxy-2,4-dinitro-biphenyl (1.2 g, 4.0 mmol) in was added at 90 ° C. over 45 minutes. The reddish brown solution was heated to reflux for 1.5 hours. The mixture was cooled to room temperature and solid NaCl (5 g) was added. This solution was extracted with CH ₂ Cl ₂ (3 × 50 mL) and the combined orange extracts were concentrated to give 2′-ethoxy-2-nitrobiphenyl-4-ylamine (0.98 g, 95%). It was. This was used in the next step without further purification.

(2′-Ethoxy-2-nitrobiphenyl-4-yl) -carbamic acid tert-butyl ester)
A mixture of 2′-ethoxy-2-nitrophenyl-4-ylamine (0.98 g, 4.0 mmol) and Boc ₂ O (2.6 g, 12 mmol) was heated with a heat gun. Once consumption of starting material was indicated by TLC, the crude mixture was purified by flash chromatography (silica gel, CH ₂ Cl ₂ ) and tert-butyl (2′-ethoxy-2-nitrobiphenyl-4-yl) -carbamate. The ester (1.5 g, 83%) was obtained.

(D-18; (2′-ethoxy-2-aminobiphenyl-4-yl) -carbamic acid tert-butyl ester)
To a solution of NiCl ₂ .6H ₂ O (0.26 g, 1.1 mmol) in EtOH (5 mL) was added NaBH ₄ (40 mg, 1.1 mmol) at −10 ° C. Gas evolution was observed and a black precipitate was formed. After stirring for 5 minutes, a solution of 2′-ethoxy-2-nitrobiphenyl-4-yl) carbamic acid tert-butyl ester (0.50 g, 1.1 mmol) in EtOH (2 mL) was added. Additional NaBH ₄ (80 mg, 60 mmol) was added in 3 portions over 20 minutes. The reaction was stirred at 0 ° C. for 20 minutes, followed by addition of NH ₄ OH (4 mL, 25% aqueous solution). The resulting solution was stirred for 20 minutes. The crude mixture was filtered through a short plug of silica. The silica cake is washed with 5% MeOH (10 mL) in CH ₂ Cl ₂ and the combined organic extracts are concentrated under reduced pressure to give (2′-ethoxy-2-aminobiphenyl-4-yl) -carbamic acid tert. -Butyl ester (D-18) (0.36 g, quantitative) was obtained. This was used without further purification. HPLC retention time 2.41 min, _10~100% CH 3 CN, 5 min gradient; ESI-MS 329.3m / z ( MH +).

  (Example 7)

(D-19; N- (3-amino-5-trifluoromethyl-phenyl) -methanesulfonamide)
A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 mmol) in pyridine (0.52 mL) and CH ₂ Cl ₂ (6.5 mL) was cooled to 0 ° C. Methanesulfonyl chloride (171 mg, 1.49 mmol) was added slowly at a rate such that the temperature of the solution remained below 10 ° C. The mixture was stirred at about 8 ° C. and then warmed to room temperature after 30 minutes. After stirring at room temperature for 4 hours, the reaction was almost complete as indicated by LCMS analysis. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 mL), extracted with CH ₂ Cl ₂ (4 × 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to N- (3- Amino-5-trifluoromethyl-phenyl) -methanesulfonamide (D-19) was obtained as a reddish brown semi-solid (0.35 g, 97%). This semi-solid was used without further purification.

(Cyclic amine)
(Example 1 :)

(7-nitro-1,2,3,4-tetrahydro-quinoline)
To a mixture of 1,2,3,4-tetrahydro-quinoline (20.0 g, 0.15 mol) dissolved in H ₂ SO ₄ (98%, 150 mL) at 0 ° C. was added KNO ₃ (18.2 g, 0 .18 mol) was added slowly. The reaction was warmed to room temperature and stirred overnight. The mixture was then poured into ice water and basified to pH 8 with saturated NaHCO ₃ solution. After extraction with CH ₂ Cl ₂ , the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10: 1) to give 7-nitro-1,2,3,4-tetrahydro-quinoline (6.6 g, 25%).

(7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester)
7-nitro-1,2,3,4-tetrahydro-quinoline (4.0 g, 5.61 mmol), Boc ₂ O (1.29 g, 5.89 mmol) and DMAP (0.4 g) in CH ₂ Cl _2. Was stirred overnight at room temperature. After dilution with water, the mixture was extracted with CH ₂ Cl ₂ . The combined organic layers are washed with NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated to give crude 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester. It was. This was used in the next step without further purification.

(DC-1; tert-butyl 7-amino-3,4-dihydroquinoline-1 (2H) -carboxylate)
Of crude 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (4.5 g, 16.2 mol) and 10% Pd-C (0.45 g) in MeOH (40 mL). The suspension was stirred overnight at room temperature under H ₂ (1 atm). After filtration, the filtrate is concentrated and the residue is purified by column chromatography (petroleum ether-EtOAc, 5: 1) to give tert-butyl 7-amino-3,4-dihydroquinoline-1 (2H) -carboxylate. (DC-1) was obtained as a brown solid (1.2 g, 22% over 2 steps).

(Example 2 :)

(3- (2-hydroxy-ethyl) -1,3-dihydro-indol-2-one)
A stirred mixture of oxindole (5.7 g, 43 mmol) and Raney nickel (10 g) in ethane-1,2-diol (100 mL) was heated in an autoclave. After the reaction was complete, the mixture was filtered and excess diol was removed under reduced pressure. The remaining oil was triturated with hexanes to give 3- (2-hydroxy-ethyl) -1,3-dihydro-indol-2-one as a colorless crystalline solid (4.6 g, 70%).

(1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indol-2-one)
To a solution of 3- (2-hydroxy-ethyl) -1,3-dihydro-indol-2-one (4.6 g, 26 mmol) and triethylamine (10 mL) in CH ₂ Cl ₂ (100 mL) was added MsCl (3. 4 g, 30 mmol) was added dropwise at -20 ° C. The mixture was then warmed to room temperature and stirred overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give crude 1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indol-2-one as a yellow solid (2.5 g). This solid was used directly in the next step.

(1,2-dihydro-3-spiro-1′-cyclopropyl-1Hindole)
To a solution of 1,2-dihydro-3-spiro-1′-cyclopropyl-1Hindol-2-one (2.5 g crude) in THF (50 mL) was added LiAlH ₄ (2 g, 52 mmol) in small portions. . After the mixture was heated to reflux, it was poured onto crushed ice, basified with aqueous ammonia to pH 8 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give crude 1,2-dihydro-3-spiro-1′-cyclopropyl-1H indole as a yellow solid (ca. 2 g). Obtained. This solid was used directly in the next step.

(6-Nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole)
To a cooled solution (−5 ° C. to −10 ° C.) of NaNO ₃ (1.3 g, 15.3 mmol) in H ₂ SO ₄ (98%, 30 mL), 1,2-dihydro-3-spiro-1′- Cyclopropyl-1H-indole (2 g, crude) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred for an additional 40 minutes and poured onto crushed ice (20 g). The cooled mixture was then basified with NH ₄ OH and extracted with EtOAc. The organic layer is washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole as a dark gray color. Obtained as a solid (1.3 g).

(1-acetyl-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole)
NaHCO ₃ (5 g) was suspended in a solution of 6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (1.3 g, crude) in CH ₂ Cl ₂ (50 mL). It became cloudy. Acetyl chloride (720 mg) was added dropwise with vigorous stirring. The mixture was stirred for 1 hour and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-acetyl-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (0.9 g over 4 steps). 15%).

(DC-2; 1-acetyl-6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1Hindole)
A mixture of 1-acetyl-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1Hindole (383 mg, 2 mmol) and Pd—C (10%, 100 mg) in EtOH (50 mL). Stir at room temperature under H ₂ (1 atm) for 1.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was treated with HCl / MeOH to give 1-acetyl-6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (DC-2) (300 mg, 90%) as hydrochloric acid. Obtained as a salt.

  (Example 3 :)

(3-Methyl-but-2-enoic acid phenylamide)
3-methyl - was heated to reflux but-2-enoic acid (100 g, 1 mol) and SOC1 ₂ (119g, 1mol) the mixture over 3 hours. Excess SOCl2 was removed under reduced pressure. CH ₂ Cl ₂ (200 mL) was added followed by aniline (93 g, 1.0 mol) in Et ₃ N (101 g, 1 mol) at 0 ° C. The mixture was stirred at room temperature for 1 hour and quenched with HCl (5%, 150 mL). The aqueous layer was separated and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated to 3-methyl-but-2-enoic acid phenylamide (120 g, 80% )

(4,4-Dimethyl-3,4-dihydro-1H-quinolin-2-one)
AlCl ₃ (500 g, 3.8 mol) was carefully added to a suspension of 3-methyl-but-2-enoic acid phenylamide (105 g, 0.6 mol) in benzene (1000 mL). The reaction mixture was stirred at 80 ° C. overnight and poured into ice water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (250 mL × 3). The combined organic layers were washed with water (200 mL × 2) and brine (200 mL), dried over Na ₂ SO ₄ and concentrated to 4,4-dimethyl-3,4-dihydro-1H-quinoline-2. -On (90 g, 86%) was obtained.

(4,4-dimethyl-1,2,3,4-tetrahydro-quinoline)
A solution of 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (35 g, 0.2 mol) in THF (100 mL) was added LiAlH ₄ (18 g in THF (200 mL) at 0 ° C. , 0.47 mol) suspension. After the addition, the mixture was stirred at room temperature for 30 minutes and then slowly heated to reflux for 1 hour. The mixture was then cooled to 0 ° C. The reaction was quenched by careful addition of water (18 mL) and NaOH solution (10%, 100 mL). The solid was filtered off and the filtrate was concentrated to give 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline.

(4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline)
To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (33 g, 0.2 mol) in H ₂ SO ₄ (120 mL) at 0 ° C. KNO ₃ (20.7 g,. 2 mol) was added slowly. After the addition, the mixture was stirred at room temperature for 2 hours, carefully poured into ice water and basified to pH 8 with Na ₂ CO ₃ . This mixture was extracted with ethyl acetate (3 × 200 mL). The combined extracts were washed with water and brine, dried over Na ₂ SO ₄ and concentrated to 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (21 g, 50 %).

(4,4-Dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tertbutyl ester)
A mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (25 g, 0.12 mol) and Boc ₂ O (55 g, 0.25 mol) was stirred at 80 ° C. for 2 days. did. The mixture was purified by silica gel chromatography to give 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (8 g, 22%).

(DC-3; tert-butyl 7-amino-3,4-dihydro-4,4-dimethylquinoline-1 (2H) -carboxylate)
4,4-Dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (8.3 g, 0.03 mol) and Pd-C (0. 5 g) was stirred overnight at room temperature under H ₂ (1 atm). The catalyst was filtered off and the filtrate was concentrated. The residue was washed with petroleum ether to give tert-butyl 7-amino-3,4-dihydro-4,4-dimethylquinoline-1 (2H) -carboxylate (DC-3) (7.2 g, 95%) Washed with.

(Example 4 :)

(1-chloro-4-methylpentan-3-one)
Ethylene was passed through a solution of isobutyryl chloride (50 g, 0.5 mol) and AlCl ₃ (68.8 g, 0.52 mol) in anhydrous CH ₂ Cl ₂ (700 mL) at 5 ° C. After 4 hours, the absorption of ethylene ceased and the mixture was stirred overnight at room temperature. The mixture was poured into cold dilute HCl solution and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude 1-chloro-4-methylpentan-3-one. This was used directly in the next step without further purification.

(4-Methyl-1- (phenylamino) -pentan-3-one)
Suspension of crude 1-chloro-4-methylpentan-3-one (about 60 g), aniline (69.8 g, 0.75 mol) and NaHCO ₃ (210 g, 2.5 mol) in CH ₃ CN (1000 mL). Was heated to reflux overnight. After cooling, the insoluble salt was filtered off and the filtrate was concentrated. The residue was diluted with H ₂ Cl ₂ and washed with 10% HCl solution (100 mL) and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give crude 4-methyl-1- (phenylamino). -Pentan-3-one was obtained.

(4-Methyl-1- (phenylamino) -pentan-3-ol)
At −10 ° C., NaBH ₄ (56.7 g, 1.5 mol) is slowly added to a mixture of crude 4-methyl-1- (phenylamino) -pentan-3-one (about 80 g) in MeOH (500 mL). Added. After the addition, the reaction mixture was warmed to room temperature and stirred for 20 minutes. The solvent was removed and the residue was partitioned between water and CH ₂ Cl ₂ . The organic layer was separated, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting gum was triturated with ether to give 4-methyl-1- (phenylamino) -pentan-3-ol as a white solid (22 g, 23%).

(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo [b] ezepin)
A mixture of 4-methyl-1- (phenylamino) -pentan-3-ol (22 g, 0.11 mol) in 98% H ₂ SO ₄ (250 mL) was stirred at 50 ° C. for 30 minutes. The reaction mixture was poured into ice water, basified with saturated NaOH solution to pH 8 and extracted with CH ₂ Cl ₂ . The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether) to give 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo [b] azepine as a brown oil (1.5 g, 8%). Obtained.

(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] ezepin)
At 0 ° C., KNO ₃ (0.76 g, 7.54 mmol) was added to 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo [b] azepine e in H ₂ SO ₄ (15 mL). Slightly added to a solution of (1.1 g, 6.28 mmol). After stirring at this temperature for 15 minutes, the mixture was poured into ice water, basified with saturated NaHCO ₃ to pH 8 and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to give crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine ( 1.2 g) was obtained. This was used directly in the next step without further purification.

(1- (5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) ethanone)
Acetyl chloride (0.77 mL, 11 mmol) was added to crude 5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine (1) in CH ₂ Cl ₂ (20 mL). 0.2 g, 5.45 mmol) and a suspension of NaHCO ₃ (1.37 g, 16.3 mmol). The mixture was heated to reflux for 1 hour. After cooling, the mixture was poured into water and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give 1- (5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo [b] azepin-1-yl) ethanone (1.05 g, 2 steps 64% in total).

(DC-4; 1- (8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo [b] azepin-1-yl) ethanone)
1- (5,5-Dimethyl-8-nitro-2,3,4,5-tetralydrobenzo [b] azepin-1-yl) ethanone (1.05 g, 40 mmol) and 10% in MeOH (20 mL) A suspension of Pd—C (0.2 g) was stirred at room temperature under H ₂ (1 atm) for 4 hours. After filtration, the filtrate was concentrated to give 1- (8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo [b] azepin-1-yl) ethanone as a white solid (DC-4) (880 mg, 94%).

(Example 5)

(Spiro [1H-indene-1,4′-piperidine] -3 (2H) -one, 1′-benzyl)
Spiro [IH-indene-1,4′-piperidine] -1′-carboxylic acid, 2,3-dihydro-3-oxo-, 1,1-dimethylethyl ester (9. Sat.) in saturated HCl / MeOH (50 mL). 50 g, 31.50 mmol) was stirred at 25 ° C. overnight. The solvent was removed under reduced pressure to give an off-white solid (7.50 g). To a solution of this solid in dry CH ₃ CN (30 mL) was added anhydrous K ₂ CO ₃ (7.85 g, 56.80 mmol). The suspension was stirred for 5 minutes and benzyl bromide (5.93 g, 34.65 mmol) was added dropwise at room temperature. The mixture was stirred for 2 hours, poured onto crushed ice and extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude spiro [1H-indene-1,4′-piperidin] -3 (2H) -one, 1′-benzyl (7.93 g). 87%). This was used without further purification.

(Spiro [1H-indene-1,4′-piperidine] -3 (2H) -one, 1′-benzyl, oxime)
To a solution of spiro [1H-indene-1,4′-piperidin] -3 (2H) -one, 1′-benzyl (7.93 g, 27.25 mmol) in EtOH (50 mL) was added hydroxylamine chloride (3 .79 g, 54.50 mmol) and anhydrous sodium acetate (4.02 g, 49.01 mmol) were added in one portion. The mixture was refluxed for 1 hour and then cooled to room temperature. The solvent was removed under reduced pressure and 200 mL of water was added. This mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ and concentrated to spiro [1H-indene-1,4′-piperidin] -3 (2H) -one, 1′benzyl, oxime (7.57 g, 91% ) This was used without further purification.

(1,2,3,4-Tetrahydroquinoline-4-spiro-4 ′-(N′-benzyl-piperidine))
To a solution of spiro [1H-indene-1,4′-piperidin] -3 (2H) -one, 1′-benzyl, oxime (7.57 g, 24.74 mmol) in dry CH ₂ Cl ₂ (150 mL), DIBAL-H (135.7 mL, 1M in toluene) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 3 hours, diluted with CH ₂ Cl ₂ (100 mL) and quenched with NaF (20.78 g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension was stirred vigorously at 0 ° C. for 30 minutes. After filtration, the residue was washed with CH ₂ Cl ₂ . The combined filtrate was concentrated under reduced pressure to give an off-brown oil. The oil was purified by column chromatography on silica gel (CH ₂ Cl ₂ -MeOH, 30: 1) to give 1,2,3,4-tetrahydroquinoline-4-spiro-4 ′-(N′-benzyl). -Piperidine) (2.72 g, 38%) was obtained.

(1,2,3,4-tetrahydroquinoline-4-spiro-4′-piperidine)
1,2,3,4-Tetrahydroquinoline-4-spiro-4 ′-(N′-benzyl-piperidine) (300 mg, 1.03 mmol) and Pd (OH) ₂ —C (30 mg) in MeOH (3 mL) The suspension of was stirred at 50 ° C. overnight under H ₂ (55 psi). After cooling, the catalyst was filtered off and washed with MeOH. The combined filtrate was concentrated under reduced pressure to give 1,2,3,4-tetrahydroquinoline-4-spiro-4′-piperidine as a white solid (176 mg, 85%). This solid was used without further purification.

(7′-nitro-spiro [piperidine-4,4 ′ (1′H) -quinoline], 2 ′, 3′-dihydro-carboxylic acid tert-butyl ester)
KNO ₃ (69.97 mg, 0.69 mmol) was added in 1,2,3,4-tetrahydroquinoline-4-spiro-4′-piperidine (133 mg, in 98% H ₂ SO ₄ (2 mL) at 0 ° C. 0.66 mmol) suspension was added in small portions. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The mixture was then poured onto crushed ice and basified to pH 8 with 10% NaOH. Boc ₂ O (172 mg, 0.79 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The mixture was then extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give crude 7′-nitro-spiro [piperidine-4,4 ′ (1′H ) -Quinoline], 2 ′, 3′-dihydro-carboxylic acid tert-butyl ester (230 mg). This was used in the next step without further purification.

(7′-nitro-spiro [piperidine-4,4 ′ (1′H) -1-acetyl-quinoline], 2 ′, 3′-dihydro-carboxylic acid tert-butyl ester)
Acetyl chloride (260 mg, 3.30 mmol) was added at room temperature to 7′-nitro-spiro [piperidine-4,4 ′ (1′H) -quinoline], 2 ′, 3′-dihydro in MeCN (5 mL). - it was added dropwise to a suspension of carboxylic acid tert- butyl ester (230 mg) and NaHCO ₃ (1.11g, 13.17mmol). The reaction mixture was refluxed for 4 hours. After cooling, the suspension was filtered and the filtrate was concentrated. The residue was purified by column chromatography (petroleum ether-EtOAc, 10: 1) to give 7′-nitro-spiro [piperidine-4,4 ′ (1′H) -1-acetyl-quinoline], 2 ′, 3. '-Dihydro-carboxylic acid tert-butyl ester (150 mg, 58% over 2 steps) was obtained.

(DC-5; 7′-amino-spiro [piperidine-4,4 ′ (1′H) -1-acetyl-quinoline], 2 ′, 3′-dihydro-carboxylic acid tert-butyl ester)
7′-nitro-spiro [piperidine-4,4 ′ (I′H) -1-acetyl-quinoline], 2 ′, 3′-dihydro-carboxylic acid tert-butyl ester (150 mg, 0) in MeOH (2 mL). .39 mmol) and Raney Ni (15 mg) suspension was stirred overnight at 25 ° C. under H ₂ (1 atm). The catalyst was removed by filtration and washed with MeOH. The combined filtrates were dried over Na ₂ SO ₄ , filtered and concentrated to 7 ′ amino-spiro [piperidine-4,4 ′ (1′H) -1-acetyl-quinoline], 2 ′, 3 ′. -Dihydro-carboxylic acid tert-butyl ester (DC-5) (133 mg, 96%) was obtained.

  (Example 7)

(2- (2,4-dinitrophenylthio) -acetic acid)
Et ₃ N (1.5 g, 15 mmol) and mercapto-acetic acid (1 g, 11 mmol) were added at room temperature to 1-chloro-2,4-dinitrobenzene (2.26 g, 1,4-dioxane (50 mL). 10 mmol) of solution. After stirring at room temperature for 5 hours, H ₂ O (100 mL) was added and the resulting suspension was extracted with ethyl acetate (100 mL × 3). The ethyl acetate extract was washed with water and brine, dried over Na ₂ SO ₄ and concentrated to give 2- (2,4-dinitrophenylthio) -acetic acid (2.3 g, 74%). This was used without further purification.

(DC-7; 6-amino-2H-benzo [b] [1,4] thiazin-3 (4H) -one)
A solution of 2- (2,4-dinitrophenylthio) -acetic acid (2.3 g, 9 mmol) and tin (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 mL) overnight. Refluxed. After removal of the solvent under reduced pressure, the remaining slurry was diluted with water (100 mL) and basified with 10% Na ₂ CO ₃ solution to a pH of 8. The resulting suspension was extracted with ethyl acetate (3 × 100 mL). The ethyl acetate extract was washed with water and brine, dried over Na ₂ SO ₄ and concentrated. The residue was washed with CH ₂ Cl ₂ to give 6-amino-2H-benzo [b] [1,4] thiazin-3 (4H) -one (DC-7) as a yellow powder (1 g, 52%). It was.

(Example 7)

(N- (2-bromo-5-nitrophenyl) acetamide)
Acetic anhydride (1.4 mL, 13.8 mmol) was added dropwise to a stirred solution of 2-bromo-5-nitroaniline (3 g, 13.8 mmol) in glacial acetic acid (30 mL) at 25 ° C. The reaction mixture was stirred at room temperature overnight and then poured into water. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give N- (2-bromo-5nitrophenyl) acetamide as an off-white solid (3.6 g, 90%).

(N- (2-bromo-5-nitrophenyl) -N- (2-methylprop-2-enyl) acetamide)
At 25 ° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) in anhydrous DMF (30 mL) was added to N- (2-bromo-5-nitrophenyl) in anhydrous DMF (50 mL). ) A solution of acetamide (3.6 g, 13.9 mmol) and potassium carbonate (3.9 g, 27.8 mmol) was added dropwise. The reaction mixture was stirred at 25 ° C. overnight. The reaction mixture was then filtered and the filtrate was treated with saturated Na ₂ CO ₃ solution. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give N- (2-bromo-5nitrophenyl) -N- (2-methylprop-2 -Enyl) acetamide as a golden solid (3.1 g, 85%). Obtained as ESI-MS 313 m / z (MH ^<+> ).

(1- (3,3-Dimethyl-6-nitroindoline-1-yl) ethanone)
N- (2-bromo-5-nitrophenyl) -N- (2-methylprop-2-enyl) acetamide (3.1 g, 10.2 mmol), tetraethylammonium chloride hydrate (2) in anhydrous DMF (50 mL) .4 g, 149 mmol), sodium formate (1.08 g, 18 mmol), sodium acetate (2.76 g, 34.2 mmol) and palladium acetate (0.32 g, 13.2 mmol) at 80 ° C. under N ₂ atmosphere. For 15 hours. After cooling, the mixture was filtered through Celite. Celite was washed with EtOAc and the combined filtrates were washed with saturated NaHCO ₃ . The separated organic layer was washed with water and brine, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give 1- (3,3-dimethyl-6-nitroindolin-1-yl) ethanone as a brown color. Obtained as a solid (2.1 g, 88%).

(DC-8; 1- (6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl) -ethanone)
10% Pd-C (0.2 g) is added to a suspension of 1- (3,3-dimethyl-6-nitroindolin-1-yl) ethanone (2.1 g, 9 mmol) in MeOH (20 mL). did. The reaction was stirred overnight at room temperature under H ₂ (40 psi). Pd-C was filtered off and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give 1- (6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl) -ethanone (DC-8) (1.3 g, 61%).

  (Example 8)

(2,3,4,5-tetrahydro-1H-benzo [b] azepine)
DIBAL (90 mL, 90 mmol) was added dropwise at 0 ° C. to a solution of 4-dihydro-2H-naphthalen-1-one oxime (3 g, 18 mmol) in dichloromethane (50 mL). The mixture was stirred at this temperature for 2 hours. The reaction was quenched with dichloromethane (30 mL) followed by treatment with NaF (2 g, 0.36 mol) and H ₂ O (5 mL, 0.27 mol). Vigorous stirring of the resulting suspension was continued for 30 minutes at 0 ° C. After filtration, the filtrate was concentrated. The residue was purified by flash column chromatography to give 2,3,4,5-tetrahydro-1H-benzo [b] azepine as a colorless oil (1.9 g, 70%).

(8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine)
At −10 ° C., 2,3,4,5-tetrahydro-1H-benzo [b] azepine (1.9 g, 13 mmol) was added to a solution of KNO ₃ (3 g, 30 mmol) in H ₂ SO ₄ (50 mL). It was dripped. The mixture was stirred for 40 minutes, poured onto crushed ice, basified with aqueous ammonia to pH 13 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to give 8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine as a black solid (1. 3 g, 51%). This was used without further purification.

(1- (8-Nitro-2,3,4,5-tetrahydro-benzo [b] azepin-1-yl) -ethanone)
Acetyl chloride (1 g, 13 mmol) was added to 8-nitro-2,3,4,5-tetrahydro-1H-benzo [b] azepine (1.3 g, 6.8 mmol) and NaHCO 3 in CH ₂ Cl ₂ (50 mL). ₃ (1 g, 12 mmol) was added dropwise. After stirring for 1 hour, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in _CH 2 Cl _2, washed with brine, dried over _Na 2 SO _4, and concentrated. The residue was purified by column chromatography to give 1- (8-nitro-2,3,4,5-tetrahydro-benzo [b] azepin-1-yl) ethanone as a yellow solid (1.3 g, 80%). Obtained.

(DC-9; 1- (8-amino-2,3,4,5-tetrahydro-benzo [b] azepin-1-yl) -ethanone)
1- (8-Nitro-2,3,4,5-tetrahydro-benzo [b] azepin-1-yl) -ethanone (1.3 g, 5.4 mmol) and Pd-C (10 in EtOH (200 mL) %, 100 mg) was stirred at room temperature under H ₂ (1 atm) for 1.5 hours. The mixture was filtered through a layer of Celite and the filtrate was concentrated to 1- (8-amino-2,3,4,5-tetrahydro-benzo [b] azepin-1-yl) -ethanone (DC-9). Was obtained as a white solid (1 g, 90%).

(Example 9)

(6-Nitro-4H-benzo [1,4] oxazin-3-one)
At 0 ° C., chloroacetyl chloride (8.75 mL, 0.11 mol) was added to 4-nitro-2-aminophenol (15.4 g, 0.1 mol), benzyltrimethylammonium chloride in chloroform (350 mL) over 30 minutes. (18.6 g, 0.1 mol) and NaHCO ₃ (42 g, 0.5 mol) were added dropwise to the mixture. After the addition, the reaction mixture was stirred at 0 ° C. for 1 hour and then at 50 ° C. overnight. The solvent was removed under reduced pressure and the residue was treated with water (50 mL). The solid was collected by filtration, washed with water, and recrystallized from ethanol to give 6-nitro-4H-benzo [1,4] oxazin-3-one as a pale yellow solid (8 g, 41%). .

(6-Nitro-3,4-dihydro-2H-benzo [1,4] oxazine)
A solution of BH ₃ .Me ₂ S in THF (2M, 7.75 mL, 15.5 mmol) was added to 6-nitro-4H-benzo [1,4] oxazin-3-one (0. 6 g, 3.1 mmol) suspension. The mixture was stirred overnight at room temperature. The reaction was quenched with MeOH (5 mL) at 0 ° C., then water (20 mL) was added. The mixture was extracted with Et ₂ O and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give 6-nitro-3,4-dihydro-2H-benzo [1, 4] Oxazine was obtained as a red solid (0.5 g, 89%). This was used without further purification.

(4-acetyl-6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine)
Under vigorous stirring at room temperature, acetyl chloride (1.02 g, 13 mmol) was added to 6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine (1 .. 1 in CH ₂ Cl ₂ (50 mL)). 8 g, 10 mmol) and NaHCO ₃ (7.14 g, 85 mmol) was added dropwise. After the addition, the reaction was stirred at this temperature for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was treated with Et ₂ O: hexane (1: 2, 50 mL) with stirring for 30 minutes, then filtered to give 4-acetyl-6-nitro-3,4-dihydro-2H-benzo [1, 4] Oxazine was obtained as a pale yellow solid (2 g, 90%).

(DC-10; 4-acetyl-6-amino-3,4-dihydro-2H-benzo [1,4] oxazine)
A mixture of 4-acetyl-6-nitro-3,4-dihydro-2H-benzo [1,4] oxazine (1.5 g, 67.6 mmol) and Pd-C (10%, 100 mg) in EtOH (30 mL). Was stirred overnight under H ₂ (1 atm). The catalyst was filtered off and the filtrate was concentrated. The residue was treated with HCl / MeOH to give 4-acetyl-6-amino-3,4-dihydro-2H-benzo [1,4] oxazine hydrochloride (DC-10) as an off-white solid (1.1 g, 85%).

(Example 10)

(1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride)
1,2,3,4-Tetrahydroisoquinoline (6.3 mL, 50.0 mmol) was added dropwise to a stirred ice-cold solution of concentrated H ₂ SO ₄ (25 mL). KNO ₃ (5.6 g, 55.0 mmol) was added in portions while maintaining the temperature below 5 ° C. The mixture was stirred at room temperature overnight, carefully poured into an ice-cold solution of concentrated NH ₄ OH and then extracted three times with CHCl ₃ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The resulting dark brown oil was dissolved in EtOH, cooled in an ice bath and treated with concentrated HCl. The yellow precipitate was collected by filtration and recrystallized from methanol to give 1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride as a yellow solid (2.5 g, 23%).

(Tert-butyl 3,4-dihydro-7-nitroisoquinoline-2 (1H) -carboxylate)
A mixture of 1,2,3,4-tetrahydro-7-nitroisoquinoline (2.5 g, 11.6 mmol), 1,4-dioxane (24 mL), H ₂ O (12 mL) and 1N NaOH (12 mL) was ice bathed. Cooled in and Boc ₂ O (2.8 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 2.5 hours, acidified with 5% KHSO ₄ solution to pH 2-3 and then extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated to give tert-butyl 3,4-dihydro-7-nitroisoquinoline-2 (1H) -carboxylate (3.3 g, quantitative). This was used without further purification.

(DC-6; tert-butyl 7-amino-3,4-dihydroisoquinoline-2 (IH) -carboxylate)
Pd (OH) ₂ (330.0 mg) was added to tert-butyl 3,4-dihydro-7-nitroisoquinoline-2 (1H) -carboxylate (3.3 g, 12 in MeOH (56 mL) under N ₂ atmosphere. 0.0 mmol) was added to the stirring solution. The reaction mixture was stirred at room temperature under H ₂ (1 atm) for 72 hours. The solid was removed by filtration through Celite. The filtrate was concentrated and purified by column chromatography (15-35% EtOAc-hexane) to give tert-butyl 7-amino-3,4-dihydroisoquinoline-2 (1H) -carboxylate (DC-6). Obtained as a pink oil (2.0 g, 69%).

(Other amines)
(Example 1 :)

(4-Bromo-3-nitrobenzonitrile)
Nitric acid (6 mL) was added dropwise at 0 ° C. to a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in concentrated H ₂ SO ₄ (10 mL). The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 2.5 hours. The resulting solution was poured into ice water. The white precipitate was collected by filtration and washed with water until the wash was neutral. The solid was recrystallized twice from an ethanol / water mixture (1: 1, 20 mL) to give 4-bromo-3-nitrobenzonitrile as a white crystalline solid (2.8 g, 56%).

(2'-ethoxy-2-nitrobiphenyl-4-carbonitrile)
To a 50 mL round bottom flask was added 4-bromo-3-nitrobenzonitrile (1.0 g, 4.4 mmol), 2-ethoxyphenylboronic acid (731 mg, 4.4 mmol), Pd ₂ (dba) ₃ (18 mg, 0 0.022 mmol) and potassium fluoride (786 mg, 13.5 mmol). The reaction vessel was evacuated and filled with argon. Dry THF (300 mL) was added followed by P (t-Bu) ₃ (0.11 mL, 10% wt. In hexane). The reaction mixture was stirred at room temperature for 30 minutes. It was then heated at 80 ° C. for 16 hours. After cooling to room temperature, the resulting mixture was filtered through a Celite pad and concentrated. 2′-Ethoxy-2-nitrobiphenyl-4-carbonitrile was isolated as a yellow solid (1.12 g, 95%).

(4-Aminomethyl-2′-ethoxy-biphenyl-2-ylamine)
To a solution of 2′-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, 1.86 mmol) in THF (80 mL) was added a solution of BH ₃ .THF (5.6 mL, 10% wt. In THF, 5.6 mmol) was added at 0 ° C. over 30 minutes. The reaction mixture was stirred at 0 ° C. for 3 hours and then at room temperature for 15 hours. The reaction solution was cooled to 0 ° C. and a H ₂ O / THF mixture (3 mL) was added. After stirring at room temperature for 6 hours, the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and extracted with 1N HCl (2 × 100 mL). The aqueous phase was basified with 1N NaOH solution to pH 1 and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated. After drying under reduced pressure, 4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine was isolated as a brown oil (370 mg, 82%).

(E-1; (2-amino-2′-ethoxy-biphenyl-4-ylmethyl) carbamic acid tert-butyl ester)
A solution of Boc ₂ O (123 mg, 0.565 mmol) in 1,4-dioxane (10 mL) was added to 4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine (1,4 dioxane (10 mL) ( 274 mg, 1.13 mmol) was added over 30 minutes. The reaction mixture was stirred at room temperature for 16 hours. Volatiles were removed on a rotary evaporator. The residue was purified by flash chromatography (silica gel, EtOAc—CH ₂ Cl ₂ , 1: 4) to give (2-amino-2′-ethoxy-biphenyl-4-ylmethyl) carbamic acid tert-butyl ester (E— 1) was obtained as a pale yellow oil (119 mg, 31%).

(Example 2 :)

(2-Bromo-1-tert-butyl-4-nitrobenzene)
Bromine (7.95 g, 50 mmol) was added dropwise to a solution of 1-tert-butyl-4-nitrobenzene (8.95 g, 50 mmol) and silver sulfate (10 g, 32 mmol) in 50 mL of 90% sulfuric acid. Stirring was continued overnight at room temperature, then the mixture was poured into dilute sodium hydrogen sulfide solution and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give 2-bromo-1-tert-t-butyl-4-nitrobenzene (12.7 g, 98%). This was used without further purification.

(2-tert-butyl-5-nitrobenzonitrile)
To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (2.13 g, 8.2 mmol) and Zn (CN) 2 mg, 6.56 mmol) in DMF (10 mL) was added Pd (PPh ₃ ) ₄ (474 mg, 0.41 mmol) was added. The mixture was heated in a sealed container at 205 ° C. for 5 hours. After cooling to room temperature, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After removal of the solvent, the residue was purified by column chromatography (0-10% EtOAc-hexane) to give 2-tert-butyl-5-nitrobenzonitrile (1,33 g, 80%).

(E-2; 2-tert-butyl-5-aminobenzonitrile)
To a refluxing solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0 mmol) in EtOH (20 mL) was added ammonium formate (816 mg, 12.6 mmol) followed by 10% Pd- C (570 mg) was added. The reaction mixture was refluxed for an additional 90 minutes, cooled to room temperature and filtered through Celite. The filtrate was concentrated to give 2-tert-butyl-5-aminobenzonitrile (E-2) (630 mg, 91%). This was used without further purification. HPLC retention time 2.66 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 175.2m / z ( MH +).

  (Example 3 :)

((2-tert-butyl-5-nitrophenyl) methanamine)
To a solution of 2-tert-butyl-5-nitrobenzonitrile (612 mg, 3.0 mmol) in THF (10 mL) was added a solution of BH ₃ .THF (12 mL, 1 M in THF, 12.0 mmol) under nitrogen. did. The reaction mixture was stirred at 70 ° C. overnight and cooled to 0 ° C. Methanol (2 mL) was added followed by 1N HCl (2 mL). After refluxing for 30 minutes, the solution was diluted with water and extracted with EtOAc. The aqueous layer was basified with 1N NaOH and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over Mg ₂ SO ₄ . After removal of the solvent, the residue was purified by column chromatography (0-10% MeOH—CH ₂ Cl ₂ ) to give (2-tert-butyl-5-nitrophenyl) methanamine (268 mg, 43%).

(Tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate)
A solution of (2-tert-butyl-5-nitrophenyl) methanamine (208 mg, 1 mmol) and Boc ₂ O (229 mg, 1.05 mmol) in THF (5 mL) was refluxed for 30 minutes. After cooling to room temperature, the solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate (240 mg, 78%). This was used without further purification.

(E-4; tert-butyl 2-tert-butyl-5-aminobenzylcarbamate)
To a solution of tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate (20 mg, 0.065 mmol) in 5% AcOH-MeOH (1 mL) was added 10% Pd-C (14 mg) under a nitrogen atmosphere. did. The mixture was stirred for 1 h at room temperature under H ₂ (1 atm). The catalyst was removed by filtration through Celite and the filtrate was concentrated to give tert-butyl 2-tert-butyl-5-aminobenzylcarbamate (E-4). This was used without further purification.

(Example 4 :)

(2-tert-butyl-5-nitrobenzoic acid)
A solution of 2-tert-butyl-5-nitrobenzonitrile (204 mg, 1 mmol) in 5 mL of 75% H ₂ SO ₄ was microwave heated at 200 ° C. for 30 minutes. The reaction mixture was poured onto ice, extracted with EtOAc, washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give 2-tert-butyl-5-nitrobenzoic acid (200 mg, 90%). This was used without further purification.

(Methyl 2-tert-butyl-5-nitrobenzoate)
To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) and K ₂ CO ₃ (147 mg, 1.1 mmol) in DMF (5.0 mL) was added CH ₃ I (40 μL,. 64 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to obtain methyl 2-tert-butyl-5-nitrobenzoate. This was used without further purification.

(E-6; methyl 2-tert-butyl-5-aminobenzoate)
To a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38 mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol) in water (1 mL) followed by 20 mg of 10% Pd-C was added. The reaction mixture was refluxed for an additional 40 minutes, cooled to room temperature, and filtered through Celite. The filtrate was concentrated to give methyl 2-tertbutyl-5-aminobenzoate (E-6) (76 mg, 95%). This was used without further purification.

(Example 5)

(2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride)
A suspension of 2-tert-butyl-5-nitrobenzenamine (0.971 g, 5 mmol) in concentrated HCl (5 mL) was cooled to 5-10 ° C. and NaNO _{2 in} H ₂ O (0.83 mL). A solution of (0.433 g, 6.3 mmol) was added dropwise. Stirring was continued for 0.5 hours, after which the mixture was vacuum filtered. The filtrate was simultaneously with a solution of Na ₂ SO ₃ (1.57 g, 12.4 mmol) in H ₂ O (2.7 mL) at 3-5 ° C. with HCl (11.7 mL) and H ₂ O (2.7 mL) ) In a stirred solution of CuSO ₄ (0.190 g, 0.76 mmol) and Na ₂ SO ₃ (1.57 g, 12.4 mmol). Stirring was continued for 0.5 hours and the resulting precipitate was filtered off, washed with water and dried to give 2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (0.235 g, 17% )

(2-tert-butyl-5-nitrobenzene-1-sulfonamide)
To a solution of 2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (100 mg, 0.36 mmol) in ether (2 mL) at 0 ° C. was added NH ₄ OH aqueous solution (128 μL, 3.6 mmol). Added. The mixture was stirred at room temperature overnight, diluted with water and extracted with ether. The combined ether extracts were washed with brine and dried over Na ₂ SO ₄ . After removal of the solvent, the residue was purified by column chromatography (0-50% EtOAc-hexane) to give 2-tert-butyl-5-nitrobenzene-1-sulfonamide (31.6 mg, 34%).

(E-7; 2-tert-butyl-5-aminobenzene-1-sulfonamide)
2-tert-butyl-5-nitro-1-sulfonamide (32 mg, 0.12 mmol) in EtOH (1.5 mL) and _{SnC1 2 · 2H 2 O (138mg} , 0.61mmol) was treated with a 100 ° C. For 30 minutes. The mixture was diluted with EtOAc and water, basified with saturated NaHCO ₃ and filtered through Celite. The organic layer was separated from the water and dried over Na ₂ SO ₄ . The solvent was removed by evaporation to give 2-tert-butyl-5-aminobenzene-1-sulfonamide (E-7) (28 mg, 100%). This was used without further purification. HPLC retention time 1.99 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 229.3m / z ( MH +).

  (Example 6)

(E-8; (2-tert-butyl-5-aminophenyl) methanol)
To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0.72 mmol) in THF (5 mL) at 0 ° C. was added LiAlH ₄ (1.4 mL, 1M in THF, 1.4 mmol). did. The reaction mixture was refluxed for 2 hours, diluted with H ₂ O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to give (2-tert-butyl-5-aminophenyl) methanol (E-8) (25 mg, 20%). This was used without further purification.

(Example 7)

(1-methyl-pyridinium monomethyl sulfate)
Methyl sulfate (30 mL, 39.8 g, 0.315 mol) was added dropwise to dry pyridine (25.0 g, 0.316 mol). The mixture was stirred at room temperature for 10 minutes and then stirred at 100 ° C. for 2 hours. The mixture was cooled to room temperature to give crude 1-methyl-pyridinium monomethyl sulfate (64.7 g, quantitative). This was used without further purification.

(1-methyl-2-pyridine)
A solution of 1-methyl-pyridinium monomethyl sulfate (50 g, 0.243 mol) in water (54 mL) was cooled to 0 ° C. Separate solutions of potassium ferricyanide (160 g, 0.486 mol) in water (320 mL) and sodium hydroxide (40 g, 1.000 mol) in water (67 mL) were prepared and from two separatory funnels 1- To a well-stirred solution of methyl-pyridinium monomethyl sulfate was added dropwise at such a rate that the temperature of the reaction mixture did not rise above 10C. The addition rate of these two solutions was adjusted so that all of the sodium hydroxide solution was introduced into the reaction mixture when half of the potassium was introduced. An iron (III) cyanide solution was added. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight. Dry sodium bicarbonate (91.6 g) was added and the mixture was stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (100 mL × 3). The combined organic layers were dried and concentrated to give 1-methyl-2-pyridone (25.0 g, 94%). This was used without further purification.

(1-methyl-3,5-dinitro-2-pyridone)
1-Methyl-2-pyridone (25.0 g, 0.229 mol) was added to sulfuric acid (500 mL) at 0 ° C. After stirring for 5 minutes, nitric acid (200 mL) was added dropwise at 0 ° C. After the addition, the reaction temperature was gradually raised to 100 ° C. and then maintained for 5 hours. The reaction mixture was poured onto ice, basified with potassium carbonate to pH 8, and extracted with CH ₂ Cl ₂ (100 mL × 3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give 1-methyl-3,5-dinitro-2-pyridone (12.5 g, 28%). This was used without further purification.

(2-Isopropyl-5-nitro-pyridine)
To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) in methyl alcohol (20 mL) was added dropwise 3-methyl-2-butanone (5.1 mL, 48 mmol) followed by A solution of ammonia in methyl alcohol (10.0 g, 17%, 100 mmol) was added dropwise. The reaction mixture was heated at 70 ° C. under atmospheric pressure for 2.5 hours. The solvent was removed under reduced pressure and the remaining oil was dissolved in CH ₂ Cl ₂ and then filtered. The filtrate was dried over Na ₂ SO ₄ and concentrated to give 2-isopropyl-5-nitro-pyridine (1.88 g, 28%).

(E-9; 2-isopropyl-5-amino-pyridine)
2-Isopropyl-5-nitro-pyridine (1.30 g, 7.82 mmol) was dissolved in methyl alcohol (20 mL) and Raney Ni (0.25 g) was added. The mixture was stirred for 2 hours at room temperature under H ₂ (1 atm). The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 2-isopropyl-5-amino-pyridine (E-9) (0.55 g, 52%).

(Example 8)

(Phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester)
To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF (350 mL) was added 2,4-di-tert-butylphenol (35 g, 169) in THF (150 mL) at 0 ° C. .6 mmol) was added dropwise. The mixture is stirred at 0 ° C. for 15 minutes and then phosphorochloridic acid (phosphochloridic).
acid) diethyl ester (30.15 g, 174.7 mmol) was added dropwise at 0 ° C. After the addition, the mixture was stirred at this temperature for 15 minutes. The reaction was quenched with saturated NH ₄ Cl (300 mL). The organic layer was separated and the aqueous phase was extracted with Et ₂ O (350 mL × 2). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude 2,4-di-tert-butyl-phenyl ester diethyl phosphate as a yellow oil (51 g, Some mineral oil was contaminated). This was used directly in the next step.

(1,3-di-tert-butyl-benzene)
NH ₃ (liquid, 250 mL) and phosphoric acid 2,4-di -tert- butyl in _Et 2 O under _{N 2} at -78 ° C. (anhydrous, 150 mL) - phenyl ester diethyl ester (51 g, final Crude from step, about 0.2 mol) was added to the solution. Small pieces of lithium metal were added to the solution until the blue color was retained. The reaction mixture was stirred at −78 ° C. for 15 minutes and then quenched with saturated NH ₄ Cl solution until the mixture was colorless. Liquid NH ₃ was evaporated and the residue was dissolved in water and extracted with Et ₂ O (300 mL × 2). The combined organic phases were dried over Na ₂ SO ₄ and concentrated to give crude 1,3-di-tert-butyl-benzene as a yellow oil (30.4 g, 94% over two steps, some mineral oil It was obtained as a messy). This was used directly in the next step.

(2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde)
To a stirred solution of 1,3-di-tert-butyl-benzene (30 g, 157.6 mmol) in dry CH ₂ Cl ₂ (700 mL) at 0 ° C. was added TiCl ₄ (37.5 g, 197 mmol). Subsequently, MeOCHCl ₂ (27.3 g, 236.4 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 1 hour. The mixture was poured into ice water and extracted with CH ₂ Cl ₂ . The combined organic phases were washed with NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (petroleum ether) to give a mixture of 2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde (21 g, 61%).

(2,4-di-tert-butyl-5-nitro-benzaldehyde and 3,5-di-tert-butyl-2-nitro-benzaldehyde)
To a mixture of 2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde in H ₂ SO ₄ (250 mL) at 0 ° C., KNO ₃ (7.64 g, 75.75 g). 6 mmol) was added in small portions. The reaction mixture was stirred at this temperature for 20 minutes and then poured onto crushed ice. The mixture was basified with NaOH solution to pH 8 and extracted with Et ₂ O (10 mL × 3). The combined organic layers were washed with water and brine and concentrated. The residue is purified by column chromatography (petroleum ether) and 2,4-di-tert-butyl-5-nitro-benzaldehyde and 3,5-di-tert-butyl-2-nitro-benzaldehyde (according to NMR). 2: 1) was obtained as a yellow solid (14.7 g, 82%). After further purification by column chromatography (petroleum ether), 2,4-di-tert-butyl-5-nitrobenzaldehyde (2.5 g, 10% 3,5-di-tert-butyl-2-nitro-benzaldehyde was Isolated).

(1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene and 1,5-di-tert-butyl-3-difluoromethyl-2-nitro-benzene)
2,4-Di-tert-butyl-5-nitro-benzaldehyde (2.4 g, 9.11 mmol, 10% 3,5-di-tert-butyl-2-l in neat deoxofluor solution. Nitro-benzaldehyde was contaminated) was stirred at room temperature for 5 hours. The reaction mixture was poured into a cooled saturated NaHCO ₃ solution and extracted with dichloromethane. The combined organics were dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (petroleum ether) to give 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene (1 1.5 g) and 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene and 1,5-di-tert-butyl-3-difluoromethyl-2-nitro-benzene (0.75 g, With 28% 1,5-di-tert-butyl-3-difluoromethyl-2-nitro-benzene).

(E-10; 1,5-di-tert-butyl-2-difluoromethyl-4-amino-benzene)
To a suspension of iron powder (5.1 g, 91.1 mmol) in 50% acetic acid (25 mL) was added 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene (1.3 g, 4.56 mmol) was added. The reaction mixture was heated at 115 ° C. for 15 minutes. The solid was filtered off and washed with acetic acid and CH ₂ Cl ₂ . The combined filtrate was concentrated and treated with HCl / MeOH. The precipitate was collected by filtration, washed with MeOH and dried to give 1,5-di-tert-butyl-2-difluoromethyl-4-amino-benzene HCl salt (E-10) as a white solid (1 .20 g, 90%).

Example 9
(General scheme :)

(Method A)
In a 2-dram vial, 2-bromoaniline (100 mg, 0.58 mmol) and the corresponding aryl boronic acid (0.82 mmol) were dissolved in THF (1 mL). H ₂ O (500 μL) was added followed by K ₂ CO ₃ (200 mg, 1.0 mmol) and Pd (PPh ₃ ) ₄ (100 mg, 0.1 mmol). The vial was purged with argon and sealed. The vial was then heated at 75 ° C. for 18 hours. The crude sample was diluted in EtOAc and filtered through a silica gel plug. The organics were concentrated by Savant Speed-vac. This crude amine was used without further purification.

(Method B)
In a 2-dram vial, the corresponding aryl boronic acid (0.58 mmol) was added followed by KF (110 mg, 1.9 mmol). The solid was suspended in THF (2 mL), then 2-bromoaniline (70 μL, 0.58 mmol) was added. The vial was purged with argon for 1 minute. Was added _{^{P (t Bu) 3 (100μL}} , 10% solution in hexane), followed by the addition of _{Pd 2 (dba) 3 (900μL} , 0.005M in THF). The vial was again purged with argon and sealed. The vial was agitated on an orbital shaker at room temperature for 30 minutes and heated in a heating block at 80 ° C. for 16 hours. The vial was then cooled to 20 ° C. and the suspension passed through a Celite pad. The pad was washed with EtOAc (5 mL). The organics were combined and concentrated under reduced pressure to give the crude amine. This crude amine was used without further purification.

  (The table below includes amines made according to the general scheme above.

(Example 10)

(Ethyl 2- (4-nitrophenyl) -2-methylpropanoate)
Sodium t-butoxide (466 mg, 4.85 mmol) was added to DMF (20 mL) at 0 ° C. The cloudy solution was cooled again to 5 ° C. Ethyl 4-nitrophenyl acetate (1.0 g, 4.78 mmol) was added. The purple slurry was cooled to 5 ° C. and methyl iodide (0.688 mL, 4.85 mmol) was added over 40 minutes. The mixture was stirred at 5-10 ° C. for 20 minutes, then sodium t-butoxide (466 mg, 4.85 mmol) and methyl iodide (0.699 mL, 4.85 mmol) were added again. The mixture was stirred at 5-10 ° C. for 20 minutes and a third charge, sodium t-butoxide (47 mg, 0.48 mmol) was added, followed by methyl iodide (0.057 mL, .0. 9 mmol) was added. Ethyl acetate (100 mL) and HCl (0.1N, 50 mL) were added. The organic layer was separated, washed with brine and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated to give ethyl 2- (4-nitrophenyl) -2-methylpropanoate (900 mg, 80%). This was used without further purification.

(G-1; ethyl 2- (4-aminophenyl) -2-methylpropanoate)
A solution of ethyl 2- (4-nitrophenyl) -2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 mL) was treated with 10% Pd—C (80 mg) and heated to 45 ° C. . A solution of potassium formate (4.10 g, 48.8 mmol) in H ₂ O (11 mL) was added over 15 minutes. The reaction mixture was stirred at 65 ° C. for 2 hours and then treated with a further 300 mg of Pd / C. The reaction was stirred for 1.5 hours and then filtered through Celite. The solvent volume was reduced by approximately 50% under reduced pressure and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure to give ethyl 2- (4-aminophenyl) -2-methylpropanoate (G-1) (670 mg, 85%). .

(Example 11)

(G-2; 2- (4-aminophenyl) -2-methylpropan-1-ol)
A solution of ethyl 2- (4-aminophenyl) -2-methylpropanoate (30 mg, 0.145 mmol) in THF (1 mL) was added LiAlH ₄ (1M solution in THF, 0.226 mL, 0. 226 mmol) and stirred for 15 minutes. The reaction was treated with 0.1N NaOH, extracted with EtOAc, and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 2- (4-aminophenyl) -2-methylpropan-1-ol (G-2). This was used without further purification:

(Example 12 :)

(2-methyl-2- (4-nitrophenyl) propanenitrile)
At 0 ° C., a suspension of sodium tert-butoxide (662 mg, 6.47 mmol) in DMF (20 mL) was treated with 4-nitrophenylacetonitrile (1000 mg, 6.18 mmol) and stirred for 10 minutes. Methyl iodide (400 μL, 6.47 mmol) was added dropwise over 15 minutes. The solution was stirred at 0-10 ° C. for 15 minutes and then at room temperature for an additional 15 minutes. To this purple solution was added sodium tert-butoxide (662 mg, 6.47 mmol) and the solution was stirred for 15 minutes. Methyl iodide (400 μL, 6.47 mmol) was challenged over 15 minutes and the solution was stirred overnight. Sodium tert-butoxide (192 mg, 1.94 mmol) was added and the reaction was stirred at 0 ° C. for 10 minutes. Methyl iodide (186 μL, 2.98 mmol) was added and the reaction was stirred for 1 hour. The reaction was then partitioned between 1N HCl (50 mL) and EtOAc (75 mL). The organic layer was washed with 1N HCl and brine, dried over Na ₂ SO ₄ and concentrated to give 2-methyl-2- (4-nitrophenyl) propanenitrile as a green waxy solid (1.25 g, 99 %).

(2-methyl-2- (4-nitrophenyl) propan-1-amine)
To a cooled solution of 2-methyl-2- (4-nitrophenyl) propanenitrile (670 mg, 3.5 mmol) in THF (15 mL), BH ₃ (1M in THF, 14 mL, 14 mmol) was added dropwise at 0 ° C. did. The mixture was warmed to room temperature and heated at 70 ° C. for 2 hours. 1N HCl solution (2 mL) was added followed by NaOH until the pH was> 7. The mixture was extracted with ether and the ether extract was concentrated to give 2-methyl-2- (4-nitrophenyl) propan-1-amine (610 mg, 90%). This was used without further purification.

(Tert-butyl 2-methyl-2- (4-nitrophenyl) propylcarbamate)
Cooled 2-methyl-2- (4-nitrophenyl) propan-1-amine (600 mg, 3.1 mmol) and 1N NaOH (3 mL, 3 mmol) in 1,4-dioxane (6 mL) and water (3 mL). To the solution at 0 ° C. was added Boc ₂ O (742 mg, 3.4 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction was acidified with 5% KHSO ₄ solution and then extracted with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated to give tert-butyl 2-methyl-2- (4nitrophenyl) propylcarbamate (725 mg, 80%). This was used without further purification.

(G-3; tert-butyl 2-methyl-2- (4-aminophenyl) propylcarbamate)
To a refluxing solution of tert-butyl 2-methyl-2- (4-nitrophenyl) propylcarbamate 725 mg, 2.5 mmol) and ammonium formate (700 mg, 10.9 mmol) in EtOH (25 mL) was added Pd-5 on carbon. % Wt (400 mg) was added. The mixture was refluxed for 1 hour, cooled, and filtered through Celite. The filtrate was concentrated to give tert-butyl 2-methyl-2- (4-aminophenyl) propylcarbamate (G-3) (550 mg, 83%). This was used without further purification.

(Example 13 :)

(7-nitro-1,2,3,4-tetrahydro-naphthalen-1-ol)
7-nitro-3,4-dihydro-2H-naphthalen-1-one (200 mg, 1.05 mmol) was dissolved in methanol (5 mL) and NaBH ₄ (78 mg, 2.05 mmol) was added in portions. The reaction was stirred at room temperature for 20 minutes, then concentrated, and purified by column chromatography (10-50% ethyl acetate-hexane) to give 7-nitro-1,2,3,4-. Tetrahydro-naphthalen-1-ol (163 mg, 80%) was obtained.

(H-1; 7-amino-1,2,3,4-tetrahydro-naphthalen-1-ol)
7-Nitro-1,2,3,4-tetrahydro - naphthalen-1-ol (142 mg, 0.73 mmol) was dissolved in methanol (10 mL), and flushed with _N 2 (g) to the flask. 10% Pd—C (10 mg) was added and the reaction was stirred at room temperature overnight under H ₂ (1 atm). The reaction was filtered and the filtrate was concentrated to give 7-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (H-1) (113 mg, 95%). HPLC retention time 0.58 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 164.5m / z ( MH +).

  (Example 14)

(7-nitro-3,4-dihydro-2H-naphthalen-1-one oxime)
To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-1-one (500 mg, 2.62 mmol) in pyridine (2 mL) was added hydroxylamine solution (1 mL, ca 50% solution in water). The reaction was stirred at room temperature for 1 hour, then concentrated and purified by column chromatography (10-50% ethyl acetate-hexane) to give 7-nitro-3,4-dihydro-2H-naphthalene- 1-one oxime (471 mg, 88%) was obtained. HPLC retention time 2.67 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 207.1m / z ( MH +).

(1,2,3,4-tetrahydro-naphthalene-1,7-diamine)
7-nitro-3,4-dihydro-2H-naphthalen-1-one oxime (274 mg, 1.33 mmol) was dissolved in methanol (10 mL) and the flask was flushed with N ₂ (g). 10% Pd—C (50 mg) was added and the reaction was stirred overnight at room temperature under H ₂ (1 atm). The reaction was filtered and the filtrate was concentrated to give 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (207 mg, 96%).

(H-2; (7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl) -carbamic acid tert-butyl ester)
To a solution of 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (154 mg, 0.95 mmol) and triethylamine (139 μL, 1.0 mmol) in methanol (2 mL) cooled to 0 ° C. was added bicarbonate. Di-tert-butyl (207 mg, 0.95 mmol) was added. The reaction was stirred at 0 ° C., then concentrated and purified by column chromatography (5-50% methanol-dichloromethane) to give (7-amino-1,2,3,4-tetrahydro-naphthalene- 1-yl) -carbamic acid tert-butyl ester (H-2) (327 mg, quantitative) was obtained. HPLC retention time 1.95 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 263.1m / z ( MH +).

  (Example 15 :)

(N- (2-bromo-benzyl) -2,2,2-trifluoro-acetamide)
To a solution of 2-bromobenzylamine (1.3 mL, 10.8 mmol) in methanol (5 mL) was added ethyl trifluoroacetate (1.54 mL, 21.6 mmol) and triethylamine (1.4 mL, 10. 8 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give N- (2-bromo-benzyl) -2,2,2-trifluoro-acetamide (3.15 g, quantitative). HPLC retention time 2.86 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 283.9m / z ( MH +).

(I-1; N- (4′-amino-biphenyl-2-ylmethyl) -2,2,2-trifluoro-acetamide)
N- (2-bromo-benzyl) -2,2,2-trifluoro-acetamide (282 mg, 1.0 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- A mixture of 2-yl) aniline (284 mg, 1.3 mmol), Pd (OAc) ₂ (20 mg, 0.09 mmol) and PS-PPh ₃ (40 mg, 3 mmol / g, 0.12 mmol) in DMF (5 mL). Dissolved and 4M K ₂ CO ₃ solution (0.5 mL) was added. The reaction was heated at 80 ° C. overnight. The mixture was filtered, concentrated and purified by column chromatography (0-50% ethyl acetate-hexane) to give N- (4′-amino-biphenyl-2-ylmethyl) -2,2,2-trimethyl. Fluoro-acetamide (I-1) (143 mg, 49%) was obtained. HPLC retention time 1.90 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 295.5m / z ( MH +).

  (Commercially available amine)

(Amide (compound of formula 1))
(General scheme:

a) Ar ₁ R7NH, coupling reagent, base, solvent. Examples of conditions used: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et ₃ N, CH ₂ Cl ₂ ; PFP-TFA, pyridine.

  (Specific examples :)

(215; 4-oxo-N-phenyl-1H-quinoline-3-carboxamide)
Solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 μL, 0.2 mmol) in DMF (1 mL) To this was added aniline (18.2 μL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The resulting solution was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45 %).

The following table lists other examples synthesized by the above general scheme.

(Indole)
(Example 1 :)
(General scheme :)

(Specific examples :)

(188-I; 6-[(4-oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid)
6-[(4-Oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid ethyl ester (188) (450 mg, 1.2 mmol) and 1N NaOH solution in THF (10 mL) (5 mL) of the mixture was stirred at 85 ° C. overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous phase is acidified with 1N HCl solution to pH 5 and the precipitate is filtered, washed with water and air dried to give 6-[(4-oxo-1H-quinolin-3-yl) carbonylamino]. -1H-indole-5-carboxylic acid (188-1) (386 mg, 93%) was obtained.

(343; N- [5- (isobutylcarbamoyl) -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide)
6-[(4-Oxo-1H-quinolin-3-yl) carbonylamino] -1H-indole-5-carboxylic acid (188-I) (26 mg, 0.08 mmol), HATU (38 mg) in DMF (1 mL). , 0.1 mmol) and DIEA (35 μL, 0.2 mmol) were added isobutylamine (7 mg, 0.1 mmol) and the reaction mixture was stirred at 65 ° C. overnight. The resulting solution was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- [5- (isobutylcarbamoyl) -1H-indol-6-yl] -4- Oxo-1H-quinoline-3-carboxamide (343) (20 mg, 66%) was obtained.

(Another example :)

(148; 4-oxo-N- [5- (1-piperidylcarbonyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide)
4-Oxo-N- [5- (1-piperidylcarbonyl) -1H-indol-6-yl] -1H-quinoline-3-carboxamide (148) is prepared according to the general scheme above for the acid (188-1) And piperidine were combined and synthesized. Overall yield (12%). HPLC retention time 2.79 min, implementation of _10~99% CH 3 CN, 5 min; ESI-MS 415.5m / z ( MH +).

(Example 2 :)
(General scheme :)

(Specific examples :)

(158; 4-oxo-N- (5-phenyl-1H-indol-6-yl) -1H-quinoline-3-carboxamide)
DMF (1 mL) N- (5-Bromo-1H-indol-6-yl) -4-oxo-1H-quinoline-3-carboxamide (B-27-1) (38 mg, 0.1 mol), phenylboronic acid ( A mixture of 18 mg, 0.15 mmol), (dppf) PdCl ₂ (catalytic amount), and K ₂ CO ₃ (100 μL, 2M solution) was heated in a microwave oven at 180 ° C. for 10 minutes. The reaction was filtered and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product 4-oxo-N- (5-phenyl-1H-indol-6-yl) -1H -Quinoline-3-carboxamide (158) (5 mg, 13%) was obtained. HPLC retention time 3.05 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 380.2m / z ( MH +).

  The following table lists other examples synthesized according to the general scheme above.

(Example 3 :)

(27; N- [1- [2- [Methyl- (2-methylaminoacetyl) -amino] acetyl] -1H-indol-6-yl] -4-oxo-1H-quinoline-3-carboxamide)
Methyl-{[methyl- (2-oxo-2- (6-[(4-oxo-1,4-dihydro-quinoline-3) dissolved in a mixture of CH ₂ Cl ₂ (50 mL) and methanol (15 mL). To a solution of -carbonyl) -amino] -indol-1-yl} -ethyl) -carbamoyl] -methyl} -carbamic acid tert-butyl ester (B-26-1) (2.0 g, 3.7 mmol) was added HCl. A solution (60 mL, 1.25 M in methanol) was added and the reaction was stirred for 64 hours at room temperature The precipitated product was collected by filtration, washed with diethyl ether and dried under high vacuum. The product N- [1- [2- [methyl- (2-methylaminoacetyl) -amino] acetyl] -1H-indol-6-yl] -4-oxo-1H-quinoli The HCl salt of N-3-carboxamide (27) was obtained as an off-white solid (1.25 g, 70%).

(Phenol)
(Example 1 :)
(General scheme :)

(Specific examples :)

(275; 4-Benzyloxy-N- (3-hydroxy-4-tert-butyl-phenyl) -quinoline-3-carboxamide)
N- (3-Hydroxy-4-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide (428) (6.7 mg, 0.02 mmol) and Cs _{2 in} DMF (0.2 mL) To a mixture of CO ₃ (13 mg, 0.04 mmol), BnBr (10 μL, 0.08 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and purified using HPLC to give 4-benzyloxy-N- (3-hydroxy-4-tert-butylphenyl) -quinoline-3-carboxamide (275).

(Another example :)

(415; N- (3-hydroxy-4-tert-butyl-phenyl) -4-methoxy-quinoline-3-carboxamide)
N- (3-Hydroxy-4-tert-butyl-phenyl) -4-methoxy-quinoline-3-carboxamide (415) is prepared according to the general scheme above for N- (3-hydroxy-4-tert-butyl-phenyl). ) -4-oxo-1H-quinoline-3-carboxamide (428) and methyl iodide were synthesized.

(Example 2 :)

(476; N- (4-tert-butyl-2-cyano-5-hydroxyphenyl) -1,4-dihydro-4-oxoquinoline-3-carboxamide)
N- (4-tert-butyl-2-bromo-5-hydroxyphenyl) -1,4-dihydro-4-oxoquinoline-3-carboxamide (C-27-1) (84 mg, 0) in NMP (1 mL) .2 mmol), Zn (CN) ₂ (14 mg, 0.12 mmol) was added Pd (PPh ₃ ) ₄ (16 mg, 0.014 mmol) under nitrogen. The mixture was heated in the high frequency range at 200 ° C. for 1 hour, filtered and purified using preparative HPLC to give N- (4-tert-butyl-2-cyano-5-hydroxyphenyl) -1 , 4-Dihydro-4-oxoquinoline-3-carboxamide (476) was obtained.

(Aniline)
(Example 1 :)
(General scheme :)

(Specific examples :)

(260; N- (5-amino-2-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide)
[3-[(4-Oxo-1H-quinolin-3-yl) carbonylamino] -4-tert-butyl-phenyl] amino formic acid tert-butyl ester (353) (33 mg, 0.08 mmol), TFA (1 mL) And a mixture of CH ₂ Cl ₂ (1 mL) was stirred at room temperature overnight. The solution is concentrated and the residue is dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- (5-amino-2-tert- Butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide (260) (15 mg, 56%) was obtained.

The following table lists other examples synthesized according to the general scheme above.

(Example 2 :)
(General scheme :)

(Specific examples :)

(485; N- (3-dimethylamino-4-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide)
CH ₂ Cl ₂ (15mL) and methanol (5 mL) solution of N- (3- amino -4-tert-butyl - phenyl) -4-oxo -1H- quinoline-3-carboxamide (271) (600mg, 1.8mmol ) Was added acetic acid (250 μL) and formaldehyde (268 μL, 3.6 mmol, 37 wt% in water). After 10 minutes, sodium cyanoborohydride (407 mg, 6.5 mmol) was added all at once. Additional formaldehyde (135 μL, 1.8 mmol, 37 wt% in water) was added at 1.5 hours and 4.2 hours. After 4.7 hours, the mixture was diluted with ether (40 mL), washed with water (25 mL) and brine (25 mL), dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting reddish brown foam was purified by preparative HPLC to give N- (3-dimethylamino-4-tert-butyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide (485) (108 mg 17%).

The following table lists other examples that are synthesized according to the general scheme above.

(Example 3 :)
(General scheme :)

(Specific examples :)

(94; N- (5-amino-2-methyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide)
Solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (50 mg, 0.26 mmol), HBTU (99 mg, 0.26 mmol) and DIEA (138 μL, 0.79 mmol) in THF (2.6 mL) To was added 2-methyl-5-nitrophenylamine (40 mg, 0.26 mmol). The mixture was heated in a microwave oven at 150 ° C. for 20 minutes and the resulting solution was concentrated. The residue was dissolved in EtOH (2 mL) and SnCl ₂ .2H ₂ O (293 mg, 1.3 mmol) was added. The reaction was stirred overnight at room temperature. The reaction mixture was basified with saturated NaHCO ₃ solution to pH 7-8 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in DMSO and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- (5-amino-2-methyl-phenyl) -4-oxo-1H-quinoline. -3-Carboxamide (94) (6 mg, 8%) was obtained. HPLC retention time 2.06 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 294.2m / z ( MH +).

  (Another example :)

(17; N- (5-amino-2-propoxy-phenyl) -4-oxo-1H-quinoline-3-carboxamide)
N- (5-amino-2-propoxy-phenyl) -4-oxo-1H-quinoline-3-carboxamide (17) was converted to 4-hydroxy-quinoline-3-carboxylic acid (A-1) and 5-nitro- Prepared according to the general scheme above starting from 2-propoxy-phenylamine. Yield (9%). HPLC retention time 3.74 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 338.3m / z ( MH +).

(Example 4 :)
(General scheme :)

(Specific examples :)

(248; N- (3-acetylamino-4-methyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide)
N- (3-amino-4-methyl-phenyl) -4-oxo-1H-quinoline-3-carboxamide (167) (33 mg, 0.11 mmol) and DIEA (49 μL, 0.28 mmol) in THF (1 mL) To the solution was added acetyl chloride (16 μL, 0.22 mmol). The reaction was stirred at room temperature for 30 minutes. LCMS analysis showed that diacylation occurred. A solution of piperidine (81 μL, 0.82 mmol) in CH ₂ Cl ₂ (2 mL) was added and the reaction was stirred for an additional 30 minutes, at which time only the desired product was detected by LCMS. The reaction solution is concentrated and the residue is dissolved in DMSO and purified by HPLC (10-99% CH ₃ CN / H ₂ O) to give the product N- (3-acetylamino-4-methyl-phenyl). ) -4-Oxo-1H-quinoline-3-carboxamide (248) (4 mg, 11%) was obtained.

The following table lists other examples synthesized by the above general scheme.

(Example 5)
(General scheme :)

(Specific examples)

(4-Oxo-N- [3- (trifluoromethyl) -5- (vinylsulfonamido) phenyl] -1,4-dihydroquinoline-3-carboxamide)
Suspension of N- [3-amino-5- (trifluoromethyl) phenyl] -4-oxo-1H-quinoline-3-carboxamide (429) (500 mg, 1.4 mmol) in 1,4-dioxane (4 mL). To the turbid was added NMM (0.4 mL, 3.6 mmol). β-chloroethylsulfonyl chloride (0.16 mL, 1.51 mmol) was added in an argon atmosphere. The mixture was stirred at room temperature for 6 and 1/2 hours, after which TLC (CH ₂ Cl ₂ -EtOAc, 8: 2) showed a new spot with an R _f very similar to the starting material. . An additional 0.5 equivalents of NMM was added and the mixture was stirred overnight at room temperature. LCMS analysis of the crude mixture showed> 85% conversion to the desired product. The mixture was concentrated, treated with 1M HCl (5 mL) and extracted with EtOAc (3 × 10 mL) and CH ₂ Cl ₂ (3 × 10 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to 4-oxo-N- [3- (trifluoromethyl) -5- (vinylsulfonamido) phenyl] -1,4. -Dihydroquinoline-3-carboxamide was obtained as an orange foam (0.495 g, 79%). This was used in the next step without further purification.

(318; 4-oxo-N- [3- [2- (1-piperidyl) ethylsulfonylamino] -5- (trifluoromethyl) phenyl] -1H-quinoline-3-carboxamide)
4-oxo-N- [3- (trifluoromethyl) -5- (vinylsulfonamido) phenyl] -1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μL, 1.6 Eq) and LiClO ₄ (20 mg, 1.7 eq) were suspended in a 1: 1 solution of CH ₂ Cl ₂ : isopropanol (1.5 mL). The mixture was refluxed at 75 ° C. for 18 hours. At this point, LCMS analysis indicated> 95% conversion to the desired product. The crude mixture was purified by reverse phase HPLC to give 4-oxo-N- [3- [2- (1-piperidyl) ethylsulfonylamino] -5- (trifluoromethyl) phenyl] -1H-quinoline-3- Carboxamide (318) was obtained as a yellowish solid (15 mg, 25%).

The table below lists other examples synthesized by the above general scheme.

(Example 6)
(General scheme :)

(Specific examples :)

(258; N-Indoline-6-yl-4-oxo-1H-quinoline-3-carboxamide)
N- (1-acetylindoline-6-yl) -4-oxo-1H-quinoline-3-carboxamide (233) (43 mg, 0.12 mmol), 1N NaOH solution (0.5 mL) and ethanol (0.5 mL) The mixture was heated to reflux for 48 hours. The solution is concentrated and the residue is dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH ₃ CN—H ₂ O) to give the product N-indoline-6-yl-4-oxo. -1H-quinoline-3-carboxamide (258) (10 mg, 20%) was obtained. HPLC retention time 2.05 min, implementation of _10~99% CH 3 CN, 5 ^{min; ESIMS 306.3m / z (MH +} ).

  The following table lists other examples synthesized by the above general scheme.

(Example 2 :)
(General scheme :)

(Specific examples :)

(299; 4-oxo-N- (1,2,3,4-tetrahydroquinolin-7-yl) -1H-quinoline-3-carboxamide)
7-[(4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester (183) (23 mg, 0.05 mmol), A mixture of TFA (1 mL) and CH ₂ Cl ₂ (1 mL) was stirred overnight at room temperature. The solution is concentrated and the residue is dissolved in DMSO (1 mL) and purified by HPLC (10-99% CH ₃ CN—H ₂ O) to give the product 4-oxo-N- (1,2, 3,4-Tetrahydroquinolin-7-yl) -1H-quinoline-3-carboxamide (299) (7 mg; 32%) was obtained. HPLC retention time 2.18 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 320.3m / z ( MH +).

  (Another example :)

(300; N- (4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl) -4-oxo-1H-quinoline-3-carboxamide)
N- (4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl) -4-oxo-1H-quinoline-3-carboxamide (300) was converted to 4,4-dimethyl-7- [ Starting from (4-oxo-1H-quinolin-3-yl) carbonylamino] -1,2,3,4-tetrahydroquinoline-1-carboxylic acid tert-butyl ester (108) according to the general scheme above Synthesized. Yield (33%).

(other)
(Example 1 :)
(General scheme :)

(Specific examples :)

(163; 4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (4-aminomethyl-2'-ethoxy-biphenyl-2-yl) -amide)
{2′-Ethoxy-2-[(4-oxo-1,4-dihydroquinoline-3-carbonyl) -amino] -biphenyl-4-ylmethyl} -carbamic acid tert-butyl ester (304) (40 mg, 0. 078 mmol) was stirred in a CH ₂ Cl ₂ / TFA mixture (3: 1, 20 mL) at room temperature for 1 h. Volatiles were removed on a rotary evaporator. The crude product was purified by preparative HPLCt to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4-aminomethyl-2′-ethoxybiphenyl-2-yl) amine (163) as tan Obtained as a solid (14 mg, 43%).

(Another example :)

(390; N- [3- (aminomethyl) -4-tert-butyl-phenyl] -4-oxo-1H-quinoline-3-carboxamide)
N- [3- (aminomethyl) -4-tert-butyl-phenyl] -4-oxo-1H-quinoline-3-carboxamide (390) is converted to [5-[(4-oxo-1H-quinoline-3- Yl) carbonylamino] -2-tert-butyl-phenyl] methylaminoformic acid tert-butyl ester (465) and was synthesized according to the general scheme above. HPLC retention time 2.44 min, gradient of _10~99% CH 3 CN, 5 min; ESI-MS m / z350.3 ( M + H) +.

(Example 2 :)
(General scheme :)

(Specific examples :)

(3- (2- (4- (1-Amino-2-methylpropan-2-yl) phenyl) acetyl) quinolin-4 (1H) -one)
(2-Methyl-2- {4- [2-oxo-2- (4-oxo-1,4-dihydro-quinolin-3-yl) -ethyl] -phenyl) -propyl) -carbamic acid tert-butyl ester (88) (0.50 g, 1.15 mmol), TFA (5 mL) and CH ₂ Cl ₂ (5 mL) were combined and stirred at room temperature overnight. The reaction mixture was then neutralized with 1N NaOH. The precipitate was collected by filtration to give the product 3- (2- (4- (1-amino-2-methylpropan-2-yl) phenyl) acetyl) quinolin-4 (1H) -one as a brown solid (651 mg 91%). HPLC retention time 2.26 min, implementation of _10~99% CH 3 CN, 5 ^{min; ESI-MS 336.5mL) (MH} +).

(323; [2-Methyl-2- [4-[(4-oxo-1H-quinolin-3-yl) carbonylamino] phenyl] -propyl] aminoformic acid methyl ester)
Methyl chloroformate (0.012 g, 0.150 mmol) was added to 3- (2- (4- (1-amino-2-methylpropan-2-yl) phenyl) acetyl) quinolin-4 (1H) -one (0 0.025 g, 0.075 mmol), TEA (0.150 mmol, 0.021 mL) and DMF (1 mL) were added and stirred at room temperature for 1 h. Piperidine (0.074 mL, 0.750 mmol) was then added and the reaction was stirred for an additional 30 minutes. The reaction mixture was filtered and purified by preparative HPLC (10-99% CH ₃ CN—H ₂ O) to give the product [2-methyl-2- [4-[(4-oxo-1H-quinoline). -3-yl) carbonylamino] phenyl] -propyl] aminoformic acid methyl ester (323) was obtained.

The following table lists other examples synthesized by the above general scheme.

(Example 3 :)
(General scheme :)

(Specific examples :)

(273-1; N- (1-aminotetralin-7-yl) -4-oxo-1H-quinoline-3-carboxamide)
A solution of [7-[(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] aminoformic acid tert-butyl ester (273) (250 mg, 0.6 mmol) in dichloromethane (2 mL) To this was added TFA (2 mL). The reaction was stirred at room temperature for 30 minutes. Additional dichloromethane (10 mL) was added to the reaction mixture and the solution was washed with saturated NaHCO ₃ solution (5 mL). A precipitate began to form in the organic layer, therefore the combined organic layers were concentrated to give N- (1-aminotetralin-7-yl) -4-oxo-1H-quinoline-3-carboxamide (273- 1) (185 mg, 93%) was obtained. HPLC retention time 1.94 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 334.5m / z ( MH +).

(159; [7-[(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid methyl ester)
N- (1-aminotetralin-7-yl) -4-oxo-1H-quinoline-3-carboxamide (273-1) (65 mg, 0.20 mmol) and DIEA (52 μL, 0.29 mmol) in methanol (1 mL) ) Was added methyl chloroformate (22 μL, 0.29 mmol). The reaction was stirred at room temperature for 1 hour. LCMS analysis of the reaction mixture showed peaks corresponding to both 1 addition product and 2 addition product. Piperidine (2 mL) was added and the reaction was stirred overnight, after which only 1 addition product was observed. The resulting solution was filtered and purified by HPLC (10-99% CH ₃ CN—H ₂ O) to give the product [7-[(4-oxo-1H-quinolin-3-yl) carbonylamino] Tetralin-1-yl] aminoformic acid methyl ester (159) (27 mg, 35%) was obtained. HPLC retention time 2.68 minutes, the implementation of _10~99% CH 3 CN, 5 min; ESI-MS 392.3m / z ( MH +).

  (Another example :)

(482; [7-[(4-oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] amino formic acid ethyl ester)
[7-[(4-Oxo-1H-quinolin-3-yl) carbonylamino] tetralin-1-yl] aminoformic acid ethyl ester (482) was prepared according to the general scheme above for amine (273-1) and chloroformate. Synthesized from ethyl acid. Overall yield (18%). HPLC retention time 2.84 min, implementation of _10~99% CH 3 CN, 5 min; ESI-MS 406.5m / z ( MH +).

  Shown below are characterization data for compounds of the present invention prepared according to the above examples.

NMR for selected compounds is shown in Table 2-A below:

(B) Assay to detect and measure AF508-CFTR corrective properties of compounds)
(I) Membrane potential optical method for assaying AF508-CFTR modulating properties of compounds)
The optical membrane potential assay is described in the voltage-sensitive FRET sensor described by Gonzalez and Tsien (Gonzalez, JE and RY Tsien (1995) “Voltage sensing by fluoresceence energy transfer JS 69”. (4): and Gonzalez, JE and RY Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence emission energy transfer”, Chem. 4: Chem. Ion probe reader (VIPR) Instrument for measuring such fluorescence change (Gonzalez, JE, K. Odes, et al. (1999) "Cell-based assays and instrumentation for screening targets- Drug targets 4 (Drug Discovery Today 4: 43). -439)).

These voltage sensitive assays are based on changes in fluorescence resonance energy transport (FRET).
The membrane soluble voltage sensitive dye DiSBAC ₂ (3) and the fluorescent phospholipid CC2-DMPE (which is bound to the outer membrane of the plasma membrane and acts as a FRET donor). Changes in membrane potential (Vm) redistribute negatively charged DiSBAC ₂ (3) across the plasma membrane and the amount of energy transfer from CC2-DMPE changes accordingly. Changes in fluorescence were monitored using VIPRTM II. This is an integrated liquid handler and fluorescence detector designed to perform cell-based screening in 96-well or 384-well microtiter plates.

(Identification of correction compounds)
In order to identify small molecules that correct the transport deficits associated with ΔF508-CFTR, a single addition HTS assay format was developed. Cells were incubated in serum-free medium for 16 hours at 37 ° C. in the presence or absence of the test compound (negative control) and, as a positive control, cells plated in 384 well plates were treated with ΔF508-CFTR. Incubated for 16 hours at 27 ° C. to “temperature-correct”. Cells were subsequently rinsed 3 times with Krebs Ringers solution and loaded with voltage sensitive dye. To activate ΔF508-CFTR, 10 μM forskolin and the CFTR enhancer genistein (20 μM) were added to each well along with medium without Cl ⁻ . C1 ^- by adding medium without, Cl in response to [Delta] F508-CFTR activation ^- is promoted efflux, resulting in membrane depolarization was optically monitored using the potentiometric sensor based dyes FRET .

(Identification of enhancer compounds)
To identify an enhancer of ΔF508-CFTR, a double-added HTS assay format was developed. In the first addition, Cl ⁻ -free medium with test compound or medium without Cl ⁻ and without test compound was added to each well. After 22 seconds, a second addition of Cl ⁻ -free medium containing 2-10 μM forskolin was added to activate ΔF508-CFTR. The extracellular Cl ⁻ concentration after both additions was 28 mM. This addition promoted Cl ⁻ efflux in response to ΔF508-CFTR activation so that membrane depolarization was optically monitored using a potentiometric sensor dye based on FRET.

(solution)
Bath solution _{(Bath Solution) # 1 (mM} ): NaCl 160, KCl 4.5, was CaCl 2 2, MgCl 2 1, HEPES 10, pH 7.4 with NaOH.

  Bath solution not containing chloride ions: The chloride salt in Bath Solution # 1 is replaced with gluconate.

  CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at −20 ° C.

DiSBAC ₂ (3): Prepared as a 10 mM stock solution in DMSO and stored at −20 ° C.

(Cell culture)
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for optical measurement of membrane potential. The cells were 2 mM glutamine, 10% fetal calf serum, 1 × NEAA, β-ME, 1 × pen / strep, 25 mM in a 175 cm ² culture flask at 37 ° C. and 90% humidity in 5% CO _2. Maintain in Dulbecco's Modified Eagle Medium supplemented with HEPES. For all optical assays, cells were seeded at 30,000 / well in a 384-well, matrigel-coated plate and incubated at 37 ° C. for 2 hours before the enhancer assay. The cells were cultured at 27 ° C. for 24 hours. For this correction assay, cells were cultured at 27 ° C. or 37 ° C. with or without test compound for 16-24 hours.

(B) Potential physiologic assay to assay ΔF508-CFTR modulating properties of compounds)
1. Ussing Chamber Assay
A Wushing chamber experiment was performed on polarized epithelial cells expressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulator identified by optical assays. FRT ^ΔF508-CFTR epithelial cells grown in Costar Snapwell cell culture inserts were transferred to a Wushing chamber (Physiological).
Instruments, Inc. , San Diego, CA), and Voltage-clamp System (Department of Bioengineering, University of Iowa, IA, and Physiological Instruments, Inc., San Layer) Processed. Transepithelial resistance was measured by applying a 2 mV pulse. Under these conditions, a resistance of 4 KΩ / cm ² or more was demonstrated in the FRT epithelium. This solution was maintained at 27 ° C. and aerated. The electrode offset potential and fluid resistance were corrected using a cell-free insert. Under these conditions, the current reflects the Cl ⁻ flow through ΔF508-CFTR expressed in the apical membrane. The I _sc, MP100A-CE interface and AcqKnowledge software; was obtained digitally by using (v3.2.6 BIOPAC Systems, Santa Barbara, CA) and.

(Identification of correction compounds)
A typical protocol utilized a Cl ⁻ concentration gradient from the basolateral membrane to the top membrane. To establish this gradient, Ringer's solution at a specified concentration is used in the basolateral membrane, while NaCl on the top membrane is replaced by an equimolar amount of sodium gluconate (titrated to pH 7.4 with NaOH). and, Cl across the epithelium ^- had a large concentration gradient. All experiments were performed using intact monolayers. To fully activate ΔF508-CFTR, forskolin (10 μM) and the PDE inhibitor IBMX (100 μM) were applied, followed by the CFTR potentiator genistein (50 μM).

As observed in other cell types, low temperature incubation of FRT cells stably expressing ΔF508-CFTR increases the density of what is functional of CFTR in the plasma membrane. In order to determine the activity of the correction compound, the cells were incubated with 10 μM of the test compound for 24 hours at 37 ° C. and then washed three times before performing the recording operation. Compound treated this cAMP-mediated and genistein-mediated I _sc in the cell and normalized to the 27 ° C. and 37 ° C. controls and expressed as activity percentages. Preincubation of this corrective compound with cells significantly increased _cAMP- and genistein-mediated Isc compared to the 37 ° C control.

(Identification of enhancer compounds)
A typical protocol utilized a Cl ⁻ concentration gradient from the basolateral membrane to the top membrane. To set this gradient, a defined concentration of Ringer's solution is used in the basolateral membrane to make the membrane permeable with nystatin (360 μg / ml), while the top membrane NaCl is equimolar in the amount of sodium gluconate ( NaOH was replaced by titrated) to pH7.4 using, Cl straddling the epithelium ^- had a large concentration gradient. All experiments were performed 30 minutes after permeabilization with nystatin. Forskolin (10 μM) and all test compounds were added to both sides of the cell culture insert. The potency of the putative ΔF508-CFTR enhancer was compared to that of genistein, a known enhancer.

(solution)
Solution for basolateral membrane (mM): NaCl (135), CaCl ₂ , MgCl ₂ (1.2), K ₂ HPO ₄ (2.4), KHPO ₄ (0.6), N-2-hydroxyethylpiperazine -N'-2-ethanesulfonic acid (HEPES) (10), and dextrose (10). This solution was titrated to pH 7.4 using NaOH.

  Top membrane solution (mM): A solution in which NaCl is replaced with sodium gluconate (135) in the same solution as the basolateral membrane solution.

(Cell culture)
Fischer rat epithelial (FRT) cells (FRT ^ΔF508-CFTR ) expressing ΔF508-CFTR were used for Wushing chamber experiments for putative ΔF508-CFTR modulators identified by our optical assay. The cells were cultured in Costar Snapwell cell culture inserts and coon supplemented with 5% fetal calf serum, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37 ° C. and 5% CO _{2 for} 5 days. (Coon) It was cultured in a modified Ham (Ham) F-12 medium. Prior to use to characterize the enhancer activity of the compounds, the cells were incubated at 27 ° C. for 16-48 hours to correct for ΔF508-CFTR. To determine the activity of the correcting compound, the cells were incubated at 27 ° C. or 37 ° C. for 24 hours with or without the test compound.

(2. Whole cell recording)
Macroscopic ΔF508-CFTR current (I _ΔF508 ) in temperature-corrected NIH3T3 cells and test compound-corrected NIH3T3 cells that stably express ΔF508-CFTR, using whole-cell recording by the perforated patch method. Monitored. Briefly, recording of I _{ΔF508 by} the voltage clamp method was performed at room temperature using an Axopatch 200B patch clamp amplifier (Axon Instrument Inc., Foster City, Calif.). All recordings were obtained at a sampling frequency of 10 kHz and low pass filtered at 1 kHz. The pipette had a resistance of 5-6 MΩ when filled with intracellular solution. Under these recording conditions, the reversal potential (E _Cl ) calculated for Cl ⁻ at room temperature was −28 mV. All records had seal resistance greater than 20 GΩ and series resistance less than 15 MΩ. Pulse generation, data acquisition, and analysis were performed using a PC equipped with Digidata 1320 A / D interface with Clampex 8 (Axon Instruments Inc.). This bath contained less than 250 μL of saline and was perfused continuously at a rate of 2 ml / min using a gravity driven perfusion system.

(Identification of correction compounds)
In order to determine the activity of the correcting compound to increase the density of functional ΔF508-CFTR in the plasma membrane, the inventors have described above to measure the current density after 24 hours of treatment with the correcting compound. A perforated patch recording technique was used. To fully activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein were added to the cells. Under our recording conditions, the current density after 24 hours incubation at 27 ° C was higher than that observed after 24 hours incubation at 37 ° C. These results are consistent with the known effect of cold incubation on the density of ΔF508-CFTR in the plasma membrane. To determine the effect of the corrective compound on the CFTR current density, the cells were incubated with 10 μM test compound for 24 hours at 37 ° C. and the current density compared to the 27 ° C. and 37 ° C. controls. (% Activity). Prior to recording, the cells were washed three times with extracellular recording medium to remove any remaining test compound. Preincubation with 10 μM corrective compound significantly increased cAMP-dependent and genistein-dependent currents compared to 37 ° C. controls.

(Identification of enhancer compounds)
The ability of ΔF508-CFTR enhancers to increase macroscopic ΔF508-CFTR Cl ⁻ current (I _ΔF508 ) in NIH3T3 cells stably expressing ΔF508-CFTR was also investigated using perforated patch recording techniques. The enhancer identified from the optical assay caused a dose-dependent increase in I _ΔF508 and similar potential and potency was observed in the optical assay. In all of the cells examined, the reverse potential before and during application of the enhancer was approximately −30 mV, as calculated E _Cl (−28 mV).

(solution)
Intracellular solution (mM): cesium aspartate (90), CsCl (50), MgCl ₂ (1), HEPES (10) and 240 μg / ml amphotericin-B (pH adjusted to 7.35 using CsOH. ing)
Extracellular solution (mM): N-methyl-D-glucamine (NMDG) -Cl (150), MgCl ₂ (2), CaCl ₂ (3), HEPES (10) (pH adjusted to 7.35 with HCl Have been).

(Cell culture)
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for whole cell recording. The cells were cultured in 2% glutamine, 10% fetal calf serum, 1 × NEAA, β-ME, 1 × pen / strep, 25 mM HEPES in a 175 cm ² culture flask at 37 ° C. and 90% humidity in 5% CO _2. Maintained in Dulbecco's modified Eagle's medium supplemented with For whole cell recording, 2,500 to 5,000 cells are seeded onto poly-L-lysine coated glass gaber slips at 27 ° C. before use to examine the activity of the enhancer. Incubate for 48 hours and incubate with or without corrective compound at 37 ° C. to determine the activity of the corrective.

(3. Single channel recording)
The single channel activity of temperature-corrected ΔF508-CFTR and the activity of the enhancer compound stably expressed in NIH3T3 cells were observed using a membrane patch that was cut out and exposed inside. Briefly, single channel active potential clamp recording was performed at room temperature using an Axopatch 200B perforated patch clamp amplifier (Axon Instruments Inc.). All recordings were obtained at a sampling frequency of 10 kHz and low pass filtered at 400 Hz. The patch pipette was made from Corning Kovar Sealing # 7052 glass (World Precision Instruments, Inc., Sarasota, FL) and has a resistance of 5-8 MΩ when filled with the extracellular solution described above. . The ΔF508-CFTR was excised and then activated by adding 1 mM Mg-ATP, as well as 75 nM cAMP-dependent protein kinase catalytic subunit (PKA; Promega Corp. Madison, WI). After channel activity was stabilized, the patch was perfused using a gravity-driven microperfusion system. Since this inflow was placed in close proximity to the patch, complete solution exchange occurred within 1-2 seconds. To maintain ΔF508-CFTR activity during rapid perfusion, a non-specific phosphatase inhibitor F ⁻ (10 mM NaF) was added to the bath solution. Under these recording conditions, channel activity was constant over the duration of the patch recording (up to 60 minutes). The current generated by the positive charge moving from the intracellular solution to the extracellular solution (anion moves in the opposite direction) is shown as a positive current. Pipette potential (Vp) was maintained at 80 mV.

Channel activity was analyzed from membrane patches containing 2 or fewer active channels. The maximum number of co-openings determined the number of active channels during the course of the experiment. To determine the amplitude of this single channel current, the 120 second recording of ΔF508-CFTR activity was filtered as “offline” at 100 Hz and then Bio-Patch Analysis software (Bio-Logic Comp., France). Was used to construct a histogram of amplitudes at all points fitted with a multi-Gaussian function. The total microscopic current and open probability (Po) were determined from the channel activity for 120 seconds. This P _o can be determined by using the Bio-Patch software, or the relationship P _o = I / i (N), where I = average current; i = single channel current amplitude, and N = activity in the patch Number of channels).

(solution)
Extracellular solution (mM): NMDG (150), aspartic acid (150), CaCl ₂ (5), MgCl ₂ (2) and HEPES (10) (pH adjusted to 7.35 with Tris base) .

Intracellular solution _{(mM): NMDG-Cl (} 150), MgCl 2 (2), EGTA (5), TES (10) and Tris base (14) (pH is adjusted to 7.35 using HCl )

(Cell culture)
NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used for excised-membrane patch-clamp recording. The cells were cultured in 2% glutamine, 10% fetal calf serum, 1 × NEAA, β-ME, 1 × pen / strep and 25 mM HEPES in a 175 cm ² culture flask at 37 ° C. and 90% humidity in 5% CO _2. Maintain in Dulbecco's Modified Eagle Medium supplemented with For single channel recording, 2,500-5,000 cells were seeded on poly-L-lysine-coated glass gaber slips and cultured at 27 ° C. for 24-48 hours prior to use.

  The compounds of the present invention are useful as modulators of ATP binding cassette transporters. Table 3 below illustrates the EC50 and relative efficacy of certain embodiments in Table 1.

  In Table 3 below, the following meanings apply: EC50: “++” means less than 10 μM; “++” means between 10 μM and 25 μM; “+” means 25 μM and 60 μM Means between.

  Efficacy%: “+” means less than 25%, “++” means 25% to 100%, and “++” means higher than 100%.

Claims (1)

The invention described herein.